Compounds and methods for reducing atxn3 expression

ABSTRACT

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 RNA in a cell or animal, and in certain embodiments reducing the amount of ATXN3 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include motor dysfunction, aggregation formation, and neuron death. Such neurodegenerative diseases include spinocerebellar ataxia type 3 (SCA3).

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0331WOSEQ_ST25.txt, created on Apr. 24, 2019, which is 680 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 RNA in a cell or animal, and in certain instances reducing the amount of Ataxin-3 protein in a cell or animal Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include spinocerebellar ataxia type 3 (SCA3).

BACKGROUND

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is caused by a mutation in the ATXN3 gene and is characterized by progressive cerebellar ataxia and variable findings including a dystonic-rigid syndrome, a parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. SCA3 is inherited in an autosomal dominant manner. Offspring of affected individuals have a 50% chance of inheriting the mutation. The diagnosis of SCA3 rests on the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in ATXN3. Affected individuals have alleles with 52 to 86 CAG trinucleotide repeats. Such testing detects 100% of affected individuals. Expanded CAG repeats in the ATXN3 gene are translated into expanded polyglutamine repeats (polyQ) in the ataxin-3 protein and this toxic ataxin-3 protein is associated with aggregates. The polyglutamine expanded ataxin-3 protein in these aggregates is ubiquinated and the aggregates contain other proteins, including heat shock proteins and transcription factors. Aggregates are frequently observed in the brain tissue of SCA3 patients. Management of SCA3 is supportive as no medication slows the course of disease; restless legs syndrome and extrapyramidal syndromes resembling parkinsonism may respond to levodopa or dopamine agonists; spasticity, drooling, and sleep problems respond variably to lioresal, atropine-like drugs, and hypnotic agents; botulinum toxin has been used for dystonia and spasticity; daytime fatigue may respond to psychostimulants such as modafinil; accompanying depression should be treated. Riess, O., Rüb), U., Pastore, A. et al. Cerebellum (2008) 7: 125.

Currently there is a lack of acceptable options for treating neurodegenerative diseases such as SCA3. It is therefore an object herein to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases.

SUMMARY OF THE INVENTION

Provided herein are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 RNA, and in certain embodiments reducing the amount of Ataxin-3 protein in a cell or animal. In certain embodiments, the animal has a neurodegenerative disease. In certain embodiments, the animal has SCA3. In certain embodiments, compounds useful for reducing expression of ATXN3 RNA are oligomeric compounds. In certain embodiments, the oligomeric compound comprises a modified oligonucleotide.

Also provided are methods useful for ameliorating at least one symptom or hallmark of a neurodegenerative disease. In certain embodiments, the neurodegenerative disease is SCA3. In certain embodiments symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. In certain embodiments, amelioration of these symptoms results in improved motor function, reduced neuropathy, and reduction in number of aggregates.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

Definitions

Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

Unless otherwise indicated, the following terms have the following meanings:

As used herein, “2′-deoxynucleoside” means a nucleoside comprising a 2′-H(H) deoxyribosyl sugar moiety, as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

As used herein, “2′-substituted nucleoside” means a nucleoside comprising a 2′-substituted sugar moiety. As used herein, “2′-substituted” in reference to a sugar moiety means a sugar moiety comprising at least one 2′-substituent group other than H or OH.

As used herein, “5-methyl cytosine” means a cytosine modified with a methyl group attached to the 5-position. A 5-methyl cytosine is a modified nucleobase.

As used herein, “administering” means providing a pharmaceutical agent to an animal.

As used herein, “animal” means a human or non-human animal.

As used herein, “antisense activity” means any detectable and/or measurable change attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound.

As used herein, “antisense compound” means an oligomeric compound capable of achieving at least one antisense activity.

As used herein, “ameliorate” in reference to a treatment means improvement in at least one symptom relative to the same symptom in the absence of the treatment. In certain embodiments, amelioration is the reduction in the severity or frequency of a symptom or the delayed onset or slowing of progression in the severity or frequency of a symptom. In certain embodiments, the symptom or hallmark is ataxia, neuropathy, and aggregate formation. In certain embodiments, amelioration of these symptoms results in improved motor function, reduced neuropathy, or reduction in number of aggregates.

As used herein, “bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety. As used herein, “bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

As used herein, “cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.

As used herein, “complementary” in reference to an oligonucleotide means that at least 70% of the nucleobases of the oligonucleotide or one or more regions thereof and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions. Complementary nucleobases means nucleobases that are capable of forming hydrogen bonds with one another. Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methyl cytosine (mC) and guanine (G). Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. As used herein, “fully complementary” or “100% complementary” in reference to oligonucleotides means that oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide.

As used herein, “conjugate group” means a group of atoms that is directly or indirectly attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.

As used herein, “conjugate linker” means a single bond or a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

As used herein, “conjugate moiety” means a group of atoms that is attached to an oligonucleotide via a conjugate linker.

As used herein, “contiguous” in the context of an oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or internucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.

As used herein, “constrained ethyl” or “cEt” or “cEt modified sugar” means a β-D ribosyl bicyclic sugar moiety wherein the second ring of the bicyclic sugar is formed via a bridge connecting the 4′-carbon and the 2′-carbon of the β-D ribosyl sugar moiety, wherein the bridge has the formula 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge is in the S configuration.

As used herein, “cEt nucleoside” means a nucleoside comprising cEt modified sugar.

As used herein, “chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

As used herein, “chirally controlled” in reference to an internucleoside linkage means chirality at that linkage is enriched for a particular stereochemical configuration.

As used herein, “gapmer” means a modified oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the “gap” and the external regions may be referred to as the “wings.” Unless otherwise indicated, “gapmer” refers to a sugar motif. Unless otherwise indicated, the sugar moieties of the nucleosides of the gap of a gapmer are unmodified 2′-deoxyribosyl. Thus, the term “MOE gapmer” indicates a gapmer having a sugar motif of 2′-MOE nucleosides in both wings and a gap of 2′-deoxynucleosides. Unless otherwise indicated, a MOE gapmer may comprise one or more modified internucleoside linkages and/or modified nucleobases and such modifications do not necessarily follow the gapmer pattern of the sugar modifications.

As used herein, “hotspot region” is a range of nucleobases on a target nucleic acid amenable to oligomeric compound-mediated reduction of the amount or activity of the target nucleic acid.

As used herein, “hybridization” means the pairing or annealing of complementary oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.

As used herein, the term “internucleoside linkage” is the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein “modified internucleoside linkage” means any internucleoside linkage other than a phosphodiester internucleoside linkage. “Phosphorothioate internucleoside linkage” is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with a sulfur atom.

As used herein, “linker-nucleoside” means a nucleoside that links, either directly or indirectly, an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of an oligomeric compound. Linker-nucleosides are not considered part of the oligonucleotide portion of an oligomeric compound even if they are contiguous with the oligonucleotide.

As used herein, “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

As used herein, “mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary with the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotide are aligned.

As used herein, “MOE” means methoxyethyl. “2′-MOE” or “2′-MOE modified sugar” means a 2′-OCH₂CH₂OCH₃ group in place of the 2′-OH group of a ribosyl sugar moiety.

As used herein, “2′-MOE nucleoside” means a nucleoside comprising a 2′-MOE modified sugar.

As used herein, “motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

As used herein, “motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

As used herein, “neurodegenerative disease” means a condition marked by progressive loss of structure or function of neurons, including death of neurons. In certain embodiments, neurodegenerative disease is spinocerebellar ataxia type 3 (SCA3).

As used herein, “nucleobase” means an unmodified nucleobase or a modified nucleobase. As used herein an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). As used herein, a “modified nucleobase” is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one unmodified nucleobase. A “5-methyl cytosine” is a modified nucleobase. A universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases. As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification.

As used herein, “nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. As used herein, “modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase. “Linked nucleosides” are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are presented between those that are linked).

As used herein, “oligomeric compound” means an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. An oligomeric compound may be paired with a second oligomeric compound that is complementary to the first oligomeric compound or may be unpaired. A “singled-stranded oligomeric compound” is an unpaired oligomeric compound. The term “oligomeric duplex” means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.”

As used herein, “oligonucleotide” means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications.

As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an animal Certain such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution, or sterile artificial cerebrospinal fluid.

As used herein “pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

As used herein “pharmaceutical composition” means a mixture of substances suitable for administering to a subject. For example, a pharmaceutical composition may comprise an oligomeric compound and a sterile aqueous solution. In certain embodiments, a pharmaceutical composition shows activity in free uptake assay in certain cell lines.

As used herein, “phosphorus moiety” means a group of atoms comprising a phosphorus atom. In certain embodiments, a phosphorus moiety comprises a mono-, di-, or tri-phosphate, or phosphorothioate.

As used herein “prodrug” means a therapeutic agent in a form outside the body that is converted to a different form within an animal or cells thereof. Typically, conversion of a prodrug within the animal is facilitated by the action of an enzyme (e.g., endogenous or viral enzyme) or chemicals present in cells or tissues and/or by physiologic conditions.

As used herein, “reducing or inhibiting the amount or activity” refers to a reduction or blockade of the transcriptional expression or activity relative to the transcriptional expression or activity in an untreated or control sample and does not necessarily indicate a total elimination of transcriptional expression or activity.

As used herein, “RNA” means an RNA transcript and includes pre-mRNA and mature mRNA unless otherwise specified.

As used herein, “RNAi compound” means an antisense compound that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics. In certain embodiments, an RNAi compound modulates the amount, activity, and/or splicing of a target nucleic acid. The term RNAi compound excludes antisense compounds that act through RNase H.

As used herein, “self-complementary” in reference to an oligonucleotide means an oligonucleotide that at least partially hybridizes to itself.

As used herein, “standard cell assay” means the assay described in Example 1 and reasonable variations thereof.

As used herein, “standard in vivo assay” means the experiment described in Example 4 and reasonable variations thereof.

As used herein, “stereorandom” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (5) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the results of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a 2′-OH(H) ribosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2′-H(H) moiety, as found in DNA (an “unmodified DNA sugar moiety”). Unmodified sugar moieties have one hydrogen at each of the 1′, 3′, and 4′ positions, an oxygen at the 3′ position, and two hydrogens at the 5′ position. As used herein, “modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate.

As used herein, “sugar surrogate” means a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or nucleic acids.

As used herein, “symptom or hallmark” means any physical feature or test result that indicates the existence or extent of a disease or disorder. In certain embodiments, a symptom is apparent to a subject or to a medical professional examining or testing said subject. In certain embodiments, a hallmark is apparent upon invasive diagnostic testing, including, but not limited to, post-mortem tests.

As used herein, “target nucleic acid” and “target RNA” mean a nucleic acid that an antisense compound is designed to affect.

As used herein, “target region” means a portion of a target nucleic acid to which an oligomeric compound is designed to hybridize.

As used herein, “terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

As used herein, “therapeutically effective amount” means an amount of a pharmaceutical agent that provides a therapeutic benefit to an animal. For example, a therapeutically effective amount improves a symptom of a disease.

CERTAIN EMBODIMENTS

The present disclosure provides the following non-limiting numbered embodiments:

Embodiment 1

An oligomeric compound, comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of an ATXN3 nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar, a sugar surrogate, and a modified internucleoside linkage.

Embodiment 2

An oligomeric compound, comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 15-2787.

Embodiment 3

An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising a portion of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases, wherein the portion is complementary to:

an equal length portion of nucleobases 138-175 of SEQ ID NO: 1;

an equal length portion of nucleobases 392-436 of SEQ ID NO: 1;

an equal length portion of nucleobases 1120-1146 of SEQ ID NO: 1;

an equal length portion of nucleobases 1823-1882 of SEQ ID NO: 1;

an equal length portion of nucleobases 3042-3098 of SEQ ID NO: 1;

an equal length portion of nucleobases 3749-3801 of SEQ ID NO: 1;

an equal length portion of nucleobases 5997-6021 of SEQ ID NO: 1;

an equal length portion of nucleobases 19437-19476 of SEQ ID NO: 2;

an equal length portion of nucleobases 34440-34486 of SEQ ID NO: 2;

an equal length portion of nucleobases 39883-39904 of SEQ ID NO: 2; or

an equal length portion of nucleobases 6597-6618 of SEQ ID NO: 2.

Embodiment 4

The oligomeric compound of any one of embodiments 1-3, wherein the ATXN3 nucleic acid has the nucleobase sequence of any of SEQ ID NOs: 1, 2, 3, 4, or 5.

Embodiment 5

The oligomeric compound of any one of embodiments 1-4, consisting of a single-stranded modified oligonucleotide.

Embodiment 6

The oligomeric compound of any one of embodiments 1-5, wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.

Embodiment 7

The oligomeric compound of embodiment 6, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

Embodiment 8

The oligomeric compound of any one of embodiments 1-5, wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.

Embodiment 9

The oligomeric compound of embodiment 8, wherein each modified internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.

Embodiment 10

The oligomeric compound of any one of embodiments 1-7, wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.

Embodiment 11

The oligomeric compound of any one of embodiments 1-7 and 10, wherein each internucleoside linkage of the modified oligonucleotide is either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.

Embodiment 12

The oligomeric compound of any one of embodiments 1-11, wherein at least one nucleobase of the modified oligonucleotide comprises a modified nucleobase.

Embodiment 13

The oligomeric compound of embodiment 12, wherein the modified nucleobase is a 5-methyl cytosine.

Embodiment 14

The oligomeric compound of any one of embodiments 1-13, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.

Embodiment 15

The oligomeric compound of embodiment 14, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.

Embodiment 16

The oligomeric compound of embodiment 15, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety having a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH2-; and —O—CH(CH3)-.

Embodiment 17

The oligomeric compound of any of embodiments 1-13, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic sugar moiety.

Embodiment 18

The oligomeric compound of embodiment 17, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified non-bicyclic sugar moiety comprising a 2′-MOE or 2′-OMe.

Embodiment 19

The oligomeric compound of embodiment 18, wherein each modified nucleoside of the modified oligonucleotide comprises a modified non-bicyclic sugar moiety comprising a 2′-MOE or 2′-OMe.

Embodiment 20

The oligomeric compound of any of embodiments 1-13, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.

Embodiment 21

The oligomeric compound of embodiment 20, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate selected from morpholino and PNA.

Embodiment 22

The oligomeric compound of any of embodiments 1-18 and 20-21, wherein the modified oligonucleotide is a gapmer.

Embodiment 23

The oligomeric compound of any of embodiments 1-18 and 20-21, wherein the modified oligonucleotide has a sugar motif comprising:

-   -   a 5′-region consisting of 1-6 linked 5′-nucleosides;     -   a central region consisting of 6-10 linked central region         nucleosides; and     -   a 3′-region consisting of 1-6 linked 5′-nucleosides; wherein         each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a modified sugar moiety and each of the         central region nucleosides comprises a 2′-deoxyribosyl sugar         moiety.

Embodiment 24

The oligomeric compound of embodiments 1-7 or 10-23, wherein the modified oligonucleotide consists of 20 linked nucleosides and has the following internucleoside motif: s000sssssssssssooss; wherein,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Embodiment 25

The oligomeric compound of any one of embodiments 1-23, wherein the modified oligonucleotide consists of 12-22, 12-20, 14-20, 16-20, 18-20, or 18-22 linked nucleosides.

Embodiment 26

The oligomeric compound of any one of embodiments 1-23 and 25, wherein the modified oligonucleotide consists of 16, 17, 18, 19, or 20 linked nucleosides.

Embodiment 27

The oligomeric compound of any of embodiments 1-26 consisting of the modified oligonucleotide.

Embodiment 28

The oligomeric compound of any of embodiments 1-26 comprising a conjugate group comprising a conjugate moiety and a conjugate linker.

Embodiment 29

The oligomeric compound of embodiment 28, wherein the conjugate group comprises a GalNAc cluster comprising 1-3 GalNAc ligands.

Embodiment 30

The oligomeric compound of embodiment 28 or 29, wherein the conjugate linker consists of a single bond.

Embodiment 31

The oligomeric compound of embodiment 28, wherein the conjugate linker is cleavable.

Embodiment 32

The oligomeric compound of embodiment 28, wherein the conjugate linker comprises 1-3 linker-nucleosides.

Embodiment 33

The oligomeric compound of any of embodiments 28-32, wherein the conjugate group is attached to the modified oligonucleotide at the 5′-end of the modified oligonucleotide.

Embodiment 34

The oligomeric compound of any of embodiments 28-32, wherein the conjugate group is attached to the modified oligonucleotide at the 3′-end of the modified oligonucleotide.

Embodiment 35

The oligomeric compound of any of embodiments 1-26 or 28-34 comprising a terminal group.

Embodiment 36

The oligomeric compound of any of embodiments 1-35 wherein the oligomeric compound is a singled-stranded oligomeric compound.

Embodiment 37

The oligomeric compound of any of embodiments 1-31 or 33-34, wherein the oligomeric compound does not comprise linker-nucleosides.

Embodiment 38

An oligomeric duplex comprising an oligomeric compound of any of embodiments 1-35 and 37.

Embodiment 39

An antisense compound comprising or consisting of an oligomeric compound of any of embodiments 1-37 or an oligomeric duplex of embodiment 38.

Embodiment 40

A modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 15-2787.

Embodiment 41

A pharmaceutical composition comprising an oligomeric compound of any of embodiments 1-37, an oligomeric duplex of embodiment 38, an antisense compound of embodiment 39, or a modified oligonucleotide of embodiment 40 and at least one of a pharmaceutically acceptable carrier or diluent.

Embodiment 42

The pharmaceutical composition of embodiment 41, wherein the modified oligonucleotide is a sodium salt.

Embodiment 43

A method comprising administering to an animal the pharmaceutical composition of any of embodiments 41-42.

Embodiment 44

The method of embodiment 43, wherein the animal is a human.

Embodiment 45

A method of treating a disease associated with ATXN3 comprising administering to an individual having or at risk for developing a disease associated with ATXN3 a therapeutically effective amount of a pharmaceutical composition of embodiments 41 and 42, and thereby treating the disease associated with ATXN3.

Embodiment 46

The method of embodiment 45, wherein the disease associated with ATXN3 is a neurodegenerative disease.

Embodiment 47

The method of embodiment 46, wherein the neurodegenerative disease is SCA3.

Embodiment 48

The method of embodiment 47, wherein at least one symptom or hallmark of the neurodegenerative disease is ameliorated.

Embodiment 49

The method of embodiment 48, wherein the symptom or hallmark is ataxia, neuropathy, and aggregate formation.

Embodiment 50

A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 51

A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 52

A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 53

A modified oligonucleotide according to the following chemical structure:

Embodiment 54

A modified oligonucleotide according to the following chemical structure:

Embodiment 55

A modified oligonucleotide according to the following chemical structure:

Embodiment 56

The modified oligonucleotide of any of embodiments 50, 52, or 54, which is a sodium salt of the formula.

Embodiment 57

A pharmaceutical composition comprising the modified oligonucleotide of any of embodiments 50-56 and a pharmaceutically acceptable carrier or diluent.

Embodiment 58

The pharmaceutical composition of embodiment 57, wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

Embodiment 59

The pharmaceutical composition of embodiment 57, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

Embodiment 60

A compound comprising a modified oligonucleotide according to the following chemical notation (5′ to 3′): Ges ^(m)Ceo Teo ^(m)Ceo Aes Tds Tds Tds Ads Tds Tds ^(m)Cds Tds ^(m)Cds Ads Aeo Geo Tes Aes ^(m)Ce (SEQ ID NO: 423), wherein,

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′ MOE sugar moiety,     -   d=a 2′-β-D deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 61

A compound comprising a modified oligonucleotide according to the following chemical notation (5′ to 3′): Ges ^(m)Ceo Aeo ^(m)Ceo ^(m)Ces Ads Tds Ads Tds Ads Tds Ads Tds ^(m)Cds Tds ^(m)Ceo Aeo Ges Aes Ae (SEQ ID NO: 1226), wherein,

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′ MOE sugar moiety,     -   d=a 2′-β-D deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 62

A compound comprising a modified oligonucleotide according to the following chemical notation (5′ to 3′): Ges Teo Teo Aeo Aes Tds Ads ^(m)Cds Tds Tds Tds Tds Tds ^(m)Cds ^(m)Cds Aeo Geo ^(m)Ces ^(m)Ces Te (SEQ ID NO: 1673), wherein,

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′ MOE sugar moiety,     -   d=a 2′-β-D deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 63

The compound of any of embodiments 60-62, comprising the modified oligonucleotide covalently linked to a conjugate group.

Embodiment 64

The compound of any of embodiment 1-63, wherein at least one internucleoside linkage of the modified oligonucleotide is chirally controlled.

Embodiment 65

The compound of any of embodiments 1-64, wherein at least one internucleoside linkage of the modified oligonucleotide is stereorandom.

Embodiment 66

A pharmaceutical composition comprising the compound of any of embodiments 60-65 and a pharmaceutically acceptable diluent or carrier.

Embodiment 67

The pharmaceutical composition of embodiment 66, wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

Embodiment 68

The pharmaceutical composition of embodiment 66, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

Embodiment 69

A chirally enriched population of modified oligonucleotides of any of embodiments 50-55, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.

Embodiment 70

The chirally enriched population of embodiment 69, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration.

Embodiment 71

The chirally enriched population of embodiment 69, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration.

Embodiment 72

The chirally enriched population of embodiment 69, wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage

Embodiment 73

The chirally enriched population of embodiment 73, wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage.

Embodiment 74

The chirally enriched population of embodiment 73, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage.

Embodiment 75

The chirally enriched population of embodiment 73, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.

Embodiment 76

The chirally enriched population of embodiment 69 or embodiment 73 wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5′ to 3′ direction.

Embodiment 77

A chirally enriched population of modified oligonucleotides of any of embodiments 50-55, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

I. Certain Oligonucleotides

In certain embodiments, provided herein are oligonucleotides, which consist of linked nucleosides. Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or may be modified oligonucleotides. Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DNA. That is, modified oligonucleotides comprise at least one modified nucleoside (comprising a modified sugar moiety and/or a modified nucleobase) and/or at least one modified internucleoside linkage.

A. Certain Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modified nucleobase or both a modified sugar moiety and a modified nucleobase.

1. Certain Sugar Moieties

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties comprising a furanosyl ring with one or more substituent groups none of which bridges two atoms of the furanosyl ring to form a bicyclic structure. Such non bridging substituents may be at any position of the furanosyl, including but not limited to substituents at the 2′, 4′, and/or 5′ positions. In certain embodiments one or more non-bridging substituent of non-bicyclic modified sugar moieties is branched. Examples of 2′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2′-F, 2′-OCH₃ (“OMe” or “O-methyl”), and 2′-O(CH₂)₂OCH₃ (“MOE”). In certain embodiments, 2′-substituent groups are selected from among: halo, allyl, amino, azido, SH, CN, OCN, CF₃, OCF₃, O—C₁-C₁₀ alkoxy, O—C₁-C₁₀ substituted alkoxy, O—C₁-C₁₀ alkyl, O—C₁-C₁₀ substituted alkyl, S-alkyl, N(R_(m))-alkyl, O-alkenyl, S-alkenyl, N(R_(m))-alkenyl, O-alkynyl, S-alkynyl, N(R_(m))-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)) or OCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat. No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al., U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. Examples of 5′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 5′-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certain embodiments, non-bicyclic modified sugar moieties comprise more than one non-bridging sugar substituent, for example, 2′-F-5′-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836.

In certain embodiments, a 2′-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂, CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substituted acetamide (OCH₂C(═O)—N(R_(m))(R_(n))), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl.

In certain embodiments, a 2′-substituted nucleoside non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, OCF₃, OCH₃, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(CH₃)₂, O(CH₂)₂O(CH₂)₂N(CH₃)₂, and OCH₂C(═O)—N(H)CH₃ (“NMA”).

In certain embodiments, a 2′-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, OCH₃, and OCH₂CH₂OCH₃.

Certain modified sugar moieties comprise a substituent that bridges two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar moiety. In certain such embodiments, the bicyclic sugar moiety comprises a bridge between the 4′ and the 2′ furanose ring atoms. Examples of such 4′ to 2′ bridging sugar substituents include but are not limited to: 4′-CH₂-2′, 4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, 4′-CH₂—O-2′ (“LNA”), 4′-CH₂—S-2′, 4′-(CH₂)₂—O-2′ (“ENA”), 4′-CH(CH₃)—O-2′ (referred to as “constrained ethyl” or “cEt”), 4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′ (“constrained MOE” or “cMOE”) and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 7,399,845, Bhat et al., U.S. Pat. No. 7,569,686, Swayze et al., U.S. Pat. No. 7,741,457, and Swayze et al., U.S. Pat. No. 8,022,193), 4′-C(CH₃)(CH₃)—O-2′ and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 8,278,283), 4′-CH₂—N(OCH₃)-2′ and analogs thereof (see, e.g., Prakash et al., U.S. Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′ (see, e.g., Allerson et al., U.S. Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745), 4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, et al., J. Org. Chem., 2009, 74, 118-134), 4′-CH₂—C(═CH₂)-2′ and analogs thereof (see e.g., Seth et al., U.S. Pat. No. 8,278,426), 4′-C(R_(a)R_(b))—N(R)—O-2′, 4′-C(R_(a)R_(b))—O—N(R)-2′, 4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O- 2′, wherein each R, R_(a), and R_(b) is, independently, H, a protecting group, or C₁-C₁₂ alkyl (see, e.g. Imanishi et al., U.S. Pat. No. 7,427,672).

In certain embodiments, such 4′ to 2′ bridges independently comprise from 1 to 4 linked groups independently selected from: —[C(R_(a))(R_(b))]_(n)—, —[C(R_(a))(R_(b))]_(n)—O—, —C(R_(a))═C(R_(b))—, —C(R_(a))═N—, —C(═NR_(a))—, —C(═O)—, —C(═S)—, —O—, —Si(R_(a))₂—, —S(═O)_(x)—, and —N(R_(a))—;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R_(a) and R_(b) is, independently, H, a protecting group, hydroxyl, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical, substituted C₅-C₇ alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁, N₃, COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)₂-J₁), or sulfoxyl (S(═O)-J₁); and

each J₁ and J₂ is, independently, H, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C₁-C₁₂ aminoalkyl, substituted C₁-C₁₂ aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443, Albaek et al., J. Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 20017, 129, 8362-8379; Wengel et a., U.S. Pat. No. 7,053,207; Imanishi et al., U.S. Pat. No. 6,268,490; Imanishi et al. U.S. Pat. No. 6,770,748; Imanishi et al., U.S. RE44,779; Wengel et al., U.S. Pat. No. 6,794,499; Wengel et al., U.S. Pat. No. 6,670,461; Wengel et al., U.S. Pat. No. 7,034,133; Wengel et al., U.S. Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel et al., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582; and Ramasamy et al., U.S. Pat. No. 6,525,191; Torsten et al., WO 2004/106356; Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181; Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No. 7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat. No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S. Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al., U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth et al., U.S. Pat. No. 8,501,805; and U.S. Patent Publication Nos. Allerson et al., US2008/0039618 and Migawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, an LNA nucleoside (described herein) may be in the α-L configuration or in the β-D configuration.

α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides have been incorporated into oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). Herein, general descriptions of bicyclic nucleosides include both isomeric configurations. When the positions of specific bicyclic nucleosides (e.g., LNA or cEt) are identified in exemplified embodiments herein, they are in the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. In certain such embodiments, the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein. For example, certain sugar surrogates comprise a 4′-sulfur atom and a substitution at the 2′-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat et al., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. For example, in certain embodiments, a sugar surrogate comprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyrans may be further modified or substituted. Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid (“MNA”) (see, e.g., Leumann, C J. Bioorg. & Med. Chem. 2002, 10, 841-854), fluoro HNA:

(“F-HNA”, see e.g. Swayze et al., U.S. Pat. No. 8,088,904; Swayze et al., U.S. Pat. No. 8,440,803; Swayze et al., U.S. Pat. No. 8,796,437; and Swayze et al., U.S. Pat. No. 9,005,906; F-HNA can also be referred to as a F-THP or 3′-fluoro tetrahydropyran), and nucleosides comprising additional modified THP compounds having the formula:

wherein, independently, for each of said modified THP nucleoside:

Bx is a nucleobase moiety;

T₃ and T₄ are each, independently, an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide or one of T₃ and T₄ is an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide and the other of T₃ and T₄ is H, a hydroxyl protecting group, a linked conjugate group, or a 5′ or 3′-terminal group;

q₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each, independently, H, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, or substituted C₂-C₆ alkynyl; and

each of R₁ and R₂ is independently selected from among: hydrogen, halogen, substituted or unsubstituted alkoxy, NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂, NJ₃C(═X)NJ₁J₂, and CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃ is, independently, H or C₁-C₆ alkyl.

In certain embodiments, modified THP nucleosides are provided wherein q₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is other than H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of R1 and R₂ is F. In certain embodiments, R₁ is F and R₂ is H, in certain embodiments, R₁ is methoxy and R₂ is H, and in certain embodiments, R₁ is methoxyethoxy and R₂ is H.

In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example, nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41, 4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton et al., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444; and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term “morpholino” means a sugar surrogate having the following structure:

In certain embodiments, morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as “modified morpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieties. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include but are not limited to: peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., WO2011/133876.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides).

2. Certain Modified Nucleobases

In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (—C═C—CH₃) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp) Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deazaadenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in Merigan et al., U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include without limitation, Manoharan et al., US2003/0158403; Manoharan et al., US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al., U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066; Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat. No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al., U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cook et al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No. 5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al., U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540; Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No. 5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S. Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook et al., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cook et al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903; Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No. 5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al., U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook et al., U.S. Pat. No. 6,166,199; and Matteucci et al., U.S. Pat. No. 6,005,096.

3. Certain Modified Internucleoside Linkages

In certain embodiments, nucleosides of modified oligonucleotides may be linked together using any internucleoside linkage. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include but are not limited to phosphates, which contain a phosphodiester bond (“P═O”) (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, and phosphorothioates (“P═S”), and phosphorodithioates (“HS—P═S”). Representative non-phosphorus containing internucleoside linking groups include but are not limited to methylenemethylimino (—CH₂—N(CH₃)—O—CH₂—), thiodiester, thionocarbamate (—O—C(═O)(NH)—S—); siloxane (—O—SiH₂—O—); and N,N′-dimethylhydrazine (—CH₂—N(CH₃)—N(CH₃)—). Modified internucleoside linkages, compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. In certain embodiments, internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art.

Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:

Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.

Neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MIMI (3′-CH₂—N(CH₃)—O-5′), amide-3 (3′-CH₂—C(═O)—N(H)-5′), amide-4 (3′-CH₂—N(H)—C(═O)-5′), formacetal (3′-O—CH2-O-5′), methoxypropyl, and thioformacetal (3′-S—CH₂—O-5′). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH₂ component parts.

B. Certain Motifs

In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified internucleoside linkage. In such embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and/or internucleoside linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties, nucleobases, and internucleoside linkages are each independent of one another. Thus, a modified oligonucleotide may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).

1. Certain Sugar Motifs

In certain embodiments, oligonucleotides comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined pattern or sugar motif. In certain instances, such sugar motifs include but are not limited to any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides comprise or consist of a region having a gapmer motif, which is defined by two external regions or “wings” and a central or internal region or “gap.” The three regions of a gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside of the 3′-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5′-wing differs from the sugar motif of the 3′-wing (asymmetric gapmer).

In certain embodiments, the wings of a gapmer comprise 1-5 nucleosides. In certain embodiments, each nucleoside of each wing of a gapmer is a modified nucleoside. In certain embodiments, each nucleoside of each wing of a gapmer is a modified nucleoside. In certain embodiments, at least one nucleoside of each wing of a gapmer is a modified nucleoside. In certain embodiments, at least two nucleosides of each wing of a gapmer are modified nucleosides. In certain embodiments, at least three nucleosides of each wing of a gapmer are modified nucleosides. In certain embodiments, at least four nucleosides of each wing of a gapmer are modified nucleosides.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides. In certain embodiments, each nucleoside of the gap of a gapmer is an unmodified 2′-deoxy nucleoside.

In certain embodiments, the gapmer is a deoxy gapmer. In embodiments, the nucleosides on the gap side of each wing/gap junction are unmodified 2′-deoxy nucleosides and the nucleosides on the wing sides of each wing/gap junction are modified nucleosides. In certain embodiments, each nucleoside of the gap is an unmodified 2′-deoxy nucleoside. In certain embodiments, each nucleoside of each wing of a gapmer is a modified nucleoside.

In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif. In such embodiments, each nucleoside of the fully modified region of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly modified comprises the same 2′-modification.

Herein, the lengths (number of nucleosides) of the three regions of a gapmer may be provided using the notation [# of nucleosides in the 5′-wing]−[# of nucleosides in the gap]−[# of nucleosides in the 3′-wing]. Thus, a 5-10-5 gapmer consists of 5 linked nucleosides in each wing and 10 linked nucleosides in the gap. Where such nomenclature is followed by a specific modification, that modification is the modification in each sugar moiety of each wing and the gap nucleosides comprise unmodified deoxynucleosides sugars. Thus, a 5-10-5 MOE gapmer consists of 5 linked MOE modified nucleosides in the 5′-wing, 10 linked deoxynucleosides in the gap, and 5 linked MOE nucleosides in the 3′-wing.

In certain embodiments, modified oligonucleotides are 5-10-5 MOE gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 BNA gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 cEt gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 LNA gapmers.

2. Certain Nucleobase Motifs

In certain embodiments, oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methyl cytosines. In certain embodiments, all of the cytosine nucleobases are 5-methyl cytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.

In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 5′-end of the oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprise a nucleoside comprising a modified nucleobase. In certain such embodiments, one nucleoside comprising a modified nucleobase is in the central gap of an oligonucleotide having a gapmer motif. In certain such embodiments, the sugar moiety of said nucleoside is a 2′-deoxyribosyl moiety. In certain embodiments, the modified nucleobase is selected from: a 2-thiopyrimidine and a 5-propynepyrimidine.

3. Certain Internucleoside Linkage Motifs

In certain embodiments, oligonucleotides comprise modified and/or unmodified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each internucleoside linking group is a phosphodiester internucleoside linkage (P═S). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is a phosphorothioate internucleoside linkage (P═S). In certain embodiments, each internucleoside linkage of a modified oligonucleotide is independently selected from a phosphorothioate internucleoside linkage and phosphodiester internucleoside linkage. In certain embodiments, each phosphorothioate internucleoside linkage is independently selected from a stereorandom phosphorothioate a (Sp) phosphorothioate, and a (Rp) phosphorothioate. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer and the internucleoside linkages within the gap are all modified. In certain such embodiments, some or all of the internucleoside linkages in the wings are unmodified phosphodiester internucleoside linkages. In certain embodiments, the terminal internucleoside linkages are modified. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer, and the internucleoside linkage motif comprises at least one phosphodiester internucleoside linkage in at least one wing, wherein the at least one phosphodiester linkage is not a terminal internucleoside linkage, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages. In certain such embodiments, all of the phosphorothioate linkages are stereorandom. In certain embodiments, all of the phosphorothioate linkages in the wings are (Sp) phosphorothioates, and the gap comprises at least one Sp, Sp, Rp motif. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising such internucleoside linkage motifs.

C. Certain Lengths

It is possible to increase or decrease the length of an oligonucleotide without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model. Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target RNA, albeit to a lesser extent than the oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.

In certain embodiments, oligonucleotides (including modified oligonucleotides) can have any of a variety of ranges of lengths. In certain embodiments, oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range. In certain such embodiments, X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; provided that X≤Y. For example, in certain embodiments, oligonucleotides consist of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 16 to 22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 17 to 18, 17 to 19, 17 to 20, 17 to 21, 17 to 22, 17 to 23, 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to 28, 17 to 29, 17 to 30, 18 to 19, 18 to 20, 18 to 21, 18 to 22, 18 to 23, 18 to 24, 18 to 25, 18 to 26, 18 to 27, 18 to 28, 18 to 29, 18 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24, 19 to 25, 19 to 26, 19 to 29, 19 to 28, 19 to 29, 19 to 30, 20 to 21, 20 to 22, 20 to 23, 20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28, 20 to 29, 20 to 30, 21 to 22, 21 to 23, 21 to 24, 21 to 25, 21 to 26, 21 to 27, 21 to 28, 21 to 29, 21 to 30, 22 to 23, 22 to 24, 22 to 25, 22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25, 23 to 26, 23 to 27, 23 to 28, 23 to 29, 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides

D. Certain Modified Oligonucleotides

In certain embodiments, the above modifications (sugar, nucleobase, internucleoside linkage) are incorporated into a modified oligonucleotide. In certain embodiments, modified oligonucleotides are characterized by their modification motifs and overall lengths. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each internucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified and may or may not follow the gapmer modification pattern of the sugar modifications. For example, the internucleoside linkages within the wing regions of a sugar gapmer may be the same or different from one another and may be the same or different from the internucleoside linkages of the gap region of the sugar motif. Likewise, such sugar gapmer oligonucleotides may comprise one or more modified nucleobase independent of the gapmer pattern of the sugar modifications. Unless otherwise indicated, all modifications are independent of nucleobase sequence.

E. Certain Populations of Modified Oligonucleotides

Populations of modified oligonucleotides in which all of the modified oligonucleotides of the population have the same molecular formula can be stereorandom populations or chirally enriched populations. All of the chiral centers of all of the modified oligonucleotides are stereorandom in a stereorandom population. In a chirally enriched population, at least one particular chiral center is not stereorandom in the modified oligonucleotides of the population. In certain embodiments, the modified oligonucleotides of a chirally enriched population are enriched for β-D ribosyl sugar moieties, and all of the phosphorothioate internucleoside linkages are stereorandom. In certain embodiments, the modified oligonucleotides of a chirally enriched population are enriched for both β-D ribosyl sugar moieties and at least one, particular phosphorothioate internucleoside linkage in a particular stereochemical configuration.

F. Nucleobase Sequence

In certain embodiments, oligonucleotides (unmodified or modified oligonucleotides) are further described by their nucleobase sequence. In certain embodiments oligonucleotides have a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain such embodiments, a region of an oligonucleotide has a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain embodiments, the nucleobase sequence of a region or entire length of an oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the second oligonucleotide or nucleic acid, such as a target nucleic acid.

II. Certain oligomeric Compounds

In certain embodiments, provided herein are oligomeric compounds, which consist of an oligonucleotide (modified or unmodified) and optionally one or more conjugate groups and/or terminal groups. Conjugate groups consist of one or more conjugate moiety and a conjugate linker which links the conjugate moiety to the oligonucleotide. Conjugate groups may be attached to either or both ends of an oligonucleotide and/or at any internal position. In certain embodiments, conjugate groups are attached to the 2′-position of a nucleoside of a modified oligonucleotide. In certain embodiments, conjugate groups that are attached to either or both ends of an oligonucleotide are terminal groups. In certain such embodiments, conjugate groups or terminal groups are attached at the 3′ and/or 5′-end of oligonucleotides. In certain such embodiments, conjugate groups (or terminal groups) are attached at the 3′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 3′-end of oligonucleotides. In certain embodiments, conjugate groups (or terminal groups) are attached at the 5′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 5′-end of oligonucleotides.

Examples of terminal groups include but are not limited to conjugate groups, capping groups, phosphate moieties, protecting groups, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified.

A. Certain Conjugate Groups

In certain embodiments, oligonucleotides are covalently attached to one or more conjugate groups. In certain embodiments, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In certain embodiments, conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide. Certain conjugate groups and conjugate moieties have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e g., do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine or hexylamino-cathonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937), a tocopherol group (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220; and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a GalNAc cluster (e.g., WO2014/179620).

1. Conjugate Moieties

Conjugate moieties include, without limitation, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.

In certain embodiments, a conjugate moiety comprises an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.

2. Conjugate Linkers

Conjugate moieties are attached to oligonucleotides through conjugate linkers. In certain oligomeric compounds, the conjugate linker is a single chemical bond (i.e., the conjugate moiety is attached directly to an oligonucleotide through a single bond). In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units.

In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain such embodiments, the conjugate linker comprises groups selected from alkyl, amino, oxo, amide and ether groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises at least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker includes at least one neutral linking group.

In certain embodiments, conjugate linkers, including the conjugate linkers described above, are bifunctional linking moieties, e.g., those known in the art to be useful for attaching conjugate groups to parent compounds, such as the oligonucleotides provided herein. In general, a bifunctional linking moiety comprises at least two functional groups. One of the functional groups is selected to bind to a particular site on a parent compound and the other is selected to bind to a conjugate group. Examples of functional groups used in a bifunctional linking moiety include but are not limited to electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups. In certain embodiments, bifunctional linking moieties comprise one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.

Examples of conjugate linkers include but are not limited to pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include but are not limited to substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl or substituted or unsubstituted C₂-C₁₀ alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

In certain embodiments, conjugate linkers comprise 1-10 linker-nucleosides. In certain embodiments, conjugate linkers comprise 2-5 linker-nucleosides. In certain embodiments, conjugate linkers comprise exactly 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise the TCA motif. In certain embodiments, such linker-nucleosides are modified nucleosides. In certain embodiments such linker-nucleosides comprise a modified sugar moiety. In certain embodiments, linker-nucleosides are unmodified. In certain embodiments, linker-nucleosides comprise an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine. In certain embodiments, a cleavable moiety is a nucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methyl cytosine, 4-N-benzoyl-5-methyl cytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typically desirable for linker-nucleosides to be cleaved from the oligomeric compound after it reaches a target tissue. Accordingly, linker-nucleosides are typically linked to one another and to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are phosphodiester bonds.

Herein, linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in embodiments in which an oligomeric compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and/or a specified percent complementarity to a reference nucleic acid and the oligomeric compound also comprises a conjugate group comprising a conjugate linker comprising linker-nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid. For example, an oligomeric compound may comprise (1) a modified oligonucleotide consisting of 8-30 nucleosides and (2) a conjugate group comprising 1-10 linker-nucleosides that are contiguous with the nucleosides of the modified oligonucleotide. The total number of contiguous linked nucleosides in such an oligomeric compound is more than 30. Alternatively, an oligomeric compound may comprise a modified oligonucleotide consisting of 8-30 nucleosides and no conjugate group. The total number of contiguous linked nucleosides in such an oligomeric compound is no more than 30. Unless otherwise indicated conjugate linkers comprise no more than 10 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 5 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 2 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 1 linker-nucleoside.

In certain embodiments, it is desirable for a conjugate group to be cleaved from the oligonucleotide. For example, in certain circumstances oligomeric compounds comprising a particular conjugate moiety are better taken up by a particular cell type, but once the oligomeric compound has been taken up, it is desirable that the conjugate group be cleaved to release the unconjugated or parent oligonucleotide. Thus, certain conjugate linkers may comprise one or more cleavable moieties. In certain embodiments, a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety is a group of atoms comprising at least one cleavable bond. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is selectively cleaved inside a cell or subcellular compartment, such as a lysosome. In certain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases.

In certain embodiments, a cleavable bond is selected from among: an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate linkage between an oligonucleotide and a conjugate moiety or conjugate group.

In certain embodiments, a cleavable moiety comprises or consists of one or more linker-nucleosides. In certain such embodiments, the one or more linker-nucleosides are linked to one another and/or to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are unmodified phosphodiester bonds. In certain embodiments, a cleavable moiety is 2′-deoxy nucleoside that is attached to either the 3′ or 5′-terminal nucleoside of an oligonucleotide by a phosphate internucleoside linkage and covalently attached to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate linkage. In certain such embodiments, the cleavable moiety is 2′-deoxyadenosine.

B. Certain Terminal Groups

In certain embodiments, oligomeric compounds comprise one or more terminal groups. In certain such embodiments, oligomeric compounds comprise a stabilized 5′-phosphate. Stabilized 5′-phosphates include, but are not limited to 5′-phosphanates, including, but not limited to 5′-vinylphosphonates. In certain embodiments, terminal groups comprise one or more abasic nucleosides and/or inverted nucleosides. In certain embodiments, terminal groups comprise one or more 2′-linked nucleosides. In certain such embodiments, the 2′-linked nucleoside is an abasic nucleoside.

III. Oligomeric Duplexes

In certain embodiments, oligomeric compounds described herein comprise an oligonucleotide, having a nucleobase sequence complementary to that of a target nucleic acid. In certain embodiments, an oligomeric compound is paired with a second oligomeric compound to form an oligomeric duplex. Such oligomeric duplexes comprise a first oligomeric compound having a region complementary to a target nucleic acid and a second oligomeric compound having a region complementary to the first oligomeric compound. In certain embodiments, the first oligomeric compound of an oligomeric duplex comprises or consists of (1) a modified or unmodified oligonucleotide and optionally a conjugate group and (2) a second modified or unmodified oligonucleotide and optionally a conjugate group. Either or both oligomeric compounds of an oligomeric duplex may comprise a conjugate group. The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides.

IV. Antisense Activity

In certain embodiments, oligomeric compounds and oligomeric duplexes are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity; such oligomeric compounds and oligomeric duplexes are antisense compounds. In certain embodiments, antisense compounds have antisense activity when they reduce or inhibit the amount or activity of a target nucleic acid by 25% or more in the standard cell assay. In certain embodiments, antisense compounds selectively affect one or more target nucleic acid. Such antisense compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired antisense activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in significant undesired antisense activity.

In certain antisense activities, hybridization of an antisense compound to a target nucleic acid results in recruitment of a protein that cleaves the target nucleic acid. For example, certain antisense compounds result in RNase H mediated cleavage of the target nucleic acid. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need not be unmodified DNA. In certain embodiments, described herein are antisense compounds that are sufficiently “DNA-like” to elicit RNase H activity. In certain embodiments, one or more non-DNA-like nucleoside in the gap of a gapmer is tolerated.

In certain antisense activities, an antisense compound or a portion of an antisense compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain antisense compounds result in cleavage of the target nucleic acid by Argonaute. Antisense compounds that are loaded into RISC are RNAi compounds. RNAi compounds may be double-stranded (siRNA) or single-stranded (ssRNA).

In certain embodiments, hybridization of an antisense compound to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain embodiments, hybridization of the antisense compound to the target nucleic acid results in alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certain embodiments, observation or detection of an antisense activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein, and/or a phenotypic change in a cell or animal.

V. Certain Target Nucleic Acids

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain such embodiments, the target nucleic acid is selected from: a mature RNA and a pre-mRNA, including intronic, exonic and untranslated regions. In certain embodiments, the target RNA is a mature mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain such embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, the target region is at least 50% within an intron. In certain embodiments, the target nucleic acid is the RNA transcriptional product of a retrogene. In certain embodiments, the target nucleic acid is a non-coding RNA. In certain such embodiments, the target non-coding RNA is selected from: a long non-coding RNA, a short non-coding RNA, an intronic RNA molecule.

A. Complementarity/Mismatches to the Target Nucleic Acid

It is possible to introduce mismatch bases without eliminating activity. For example, Gautschi et al (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo. Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358, 1988) tested a series of tandem 14 nucleobase oligonucleotides, and 28 and 42 nucleobase oligonucleotides comprised of the sequence of two or three of the tandem oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 nucleobase oligonucleotides.

In certain embodiments, oligonucleotides that are complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, oligonucleotides are 99%, 95%, 90%, 85%, or 80% complementary to the target nucleic acid. In certain embodiments, oligonucleotides are at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide and comprise a region that is 100% or fully complementary to a target nucleic acid. In certain embodiments, the region of full complementarity is from 6 to 20, 10 to 18, or 18 to 20 nucleobases in length.

In certain embodiments, oligonucleotides comprise one or more mismatched nucleobases relative to the target nucleic acid. In certain embodiments, antisense activity against the target is reduced by such mismatch, but activity against a non-target is reduced by a greater amount. Thus, in certain embodiments selectivity of the oligonucleotide is improved. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide having a gapmer motif. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8 from the 5′-end of the gap region. In certain embodiments, the mismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3′-end of the gap region. In certain embodiments, the mismatch is at position 1, 2, 3, or 4 from the 5′-end of the wing region. In certain embodiments, the mismatch is at position 4, 3, 2, or 1 from the 3′-end of the wing region.

B. ATXN3

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid, wherein the target nucleic acid is ATXN3. In certain embodiments, ATXN3 nucleic acid has the sequence set forth in SEQ ID NO: 1 (GENBANK Accession No: NM_004993.5); SEQ ID NO: 2 (the complement of GENBANK Accession No NC_000014.9 truncated from nucleotides 92,056,001 to 92,110,000); SEQ ID NO: 3 (GENBANK Accession No: NM_001164781.1); SEQ ID NO: 4 (GENBANK Accession No: NM_001127697.2); and SEQ ID NO: 5 (ensemble transcript No: ENST00000558190.5).

In certain embodiments, contacting a cell with an oligomeric compound complementary to any of SEQ ID NOs: 1-5 reduces the amount of ATXN3 RNA, and in certain embodiments reduces the amount of Ataxin-3 protein. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide. In certain embodiments, contacting a cell in an animal with an oligomeric compound complementary to any of SEQ ID NOs: 1-5 ameliorate one or more symptom or hallmark of a neurodegenerative disease. In certain embodiments, the symptom or hallmark is ataxia, neuropathy, and aggregate formation. In certain embodiments, contacting a cell in an animal with an oligonucleotide complementary to any of SEQ ID Nos: 1-5 results in improved motor function, reduced neuropathy, and/or reduction in number of aggregates. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide.

C. Certain Target Nucleic Acids in Certain Tissues

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid, wherein the target nucleic acid is expressed in a pharmacologically relevant tissue. In certain embodiments, the pharmacologically relevant tissues are the cells and tissues that comprise the central nervous system (CNS), including spinal cord, cortex, cerebellum, brain stem, and pons.

VI. Certain Pharmaceutical Compositions

In certain embodiments, described herein are pharmaceutical compositions comprising one or more oligomeric compounds. In certain embodiments, the one or more oligomeric compounds each consists of a modified oligonucleotide. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutical composition comprises or consists of a sterile saline solution and one or more oligomeric compound. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and sterile water. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and phosphate-buffered saline (PBS). In certain embodiments, the sterile PBS is pharmaceutical grade PBS. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.

In certain embodiments, a pharmaceutical composition comprises a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists essentially of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.

In certain embodiments, pharmaceutical compositions comprise one or more oligomeric compound and one or more excipients. In certain embodiments, excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.

In certain embodiments, oligomeric compounds may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

In certain embodiments, pharmaceutical compositions comprising an oligomeric compound encompass any pharmaceutically acceptable salts of the oligomeric compound, esters of the oligomeric compound, or salts of such esters. In certain embodiments, pharmaceutical compositions comprising oligomeric compounds comprising one or more oligonucleotide, upon administration to an animal, including a human, are capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of oligomeric compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. In certain embodiments, prodrugs comprise one or more conjugate group attached to an oligonucleotide, wherein the conjugate group is cleaved by endogenous nucleases within the body.

Lipid moieties have been used in nucleic acid therapies in a variety of methods. In certain such methods, the nucleic acid, such as an oligomeric compound, is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In certain methods, DNA complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to a particular cell or tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to fat tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to muscle tissue.

In certain embodiments, pharmaceutical compositions comprise a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.

In certain embodiments, pharmaceutical compositions comprise one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents of the present invention to specific tissues or cell types. For example, in certain embodiments, pharmaceutical compositions include liposomes coated with a tissue-specific antibody.

In certain embodiments, pharmaceutical compositions comprise a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

In certain embodiments, pharmaceutical compositions are prepared for oral administration. In certain embodiments, pharmaceutical compositions are prepared for buccal administration. In certain embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV), etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain.

Under certain conditions, certain compounds disclosed herein act as acids. Although such compounds may be drawn or described in protonated (free acid) form, in ionized (anion) form, or ionized and in association with a cation (salt) form, aqueous solutions of such compounds exist in equilibrium among such forms. For example, a phosphate linkage of an oligonucleotide in aqueous solution exists in equilibrium among free acid, anion, and salt forms. Unless otherwise indicated, compounds described herein are intended to include all such forms. Moreover, certain oligonucleotides have several such linkages, each of which is in equilibrium. Thus, oligonucleotides in solution exist in an ensemble of forms at multiple positions all at equilibrium. The term “oligonucleotide” is intended to include all such forms. Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms. Herein, a structure depicting the free acid of a compound followed by the term “or salts thereof” expressly includes all such forms that may be fully or partially protonated/de-protonated/in association with a cation. In certain instances, one or more specific cation is identified.

In certain embodiments, modified oligonucleotides are in aqueous solution with sodium. In certain embodiments, modified oligonucleotides are in aqueous solution with potassium. In certain embodiments, modified oligonucleotides are in PBS. In certain embodiments, modified oligonucleotides are in water. In certain such embodiments, the pH of the solution is adjusted with NaOH and/or HCl to achieve a desired pH.

VII. Certain Compositions

1. Compound No. 1100673

In certain embodiments, Compound No. 1100673 is characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) GCTCATTTATTCTCAAGTAC (SEQ ID NO: 423), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE sugar moiety and each of nucleosides 6-15 are 2′13-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1100673 is represented by the following chemical notation (5′ to 3′): Ges ^(m)Ceo Teo ^(m)Ceo Aes Tds Tds Tds Ads Tds Tds ^(m)Cds Tds ^(m)Cds Ads Aeo Geo Tes Aes ^(m)Ce (SEQ ID NO: 423), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′ MOE sugar moiety,

d=a 2′-β-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1100673 is represented by the following chemical structure:

In certain embodiments, the sodium salt of Compound No. 1100673 is represented by the following chemical structure:

2. Compound No. 1101657

In certain embodiments, Compound No. 1101657 is characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) GCACCATATATATCTCAGAA (SEQ ID NO: 1226), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE sugar moiety and each of nucleosides 6-15 are 2′13-D-deoxynucleosides (from 5′ to 3′), wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages (from 5′ to 3′) and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages (from 5′ to 3′), and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1101657 is represented by the following chemical notation (5′ to 3′): Ges ^(m)Ceo Aeo ^(m)Ceo ^(m)Ces Ads Tds Ads Tds Ads Tds Ads Tds ^(m)Cds Tds ^(m)Ceo Aeo Ges Aes Ae (SEQ ID NO: 1226), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′ MOE sugar moiety,

d=a 2′-β-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1101657 is represented by the following chemical structure:

In certain embodiments, the sodium salt of Compound No. 1101657 is represented by the following chemical structure:

3. Compound No. 1102130

In certain embodiments, Compound No. 1102130 is characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) GTTAATACTTTTTCCAGCCT (SEQ ID NO: 1673), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE sugar moiety and each of nucleosides 6-15 are 2′13-D-deoxynucleosides (from 5′ to 3′), wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages (from 5′ to 3′) and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages (from 5′ to 3′), and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1102130 is represented by the following chemical notation (5′ to 3′): Ges Teo Teo Aeo Aes Tds Ads ^(m)Cds Tds Tds Tds Tds Tds ^(m)Cds ^(m)Cds Aeo Geo ^(m)Ces ^(m)Ces Te (SEQ ID NO: 1673), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′ MOE sugar moiety,

d=a 2′13-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1102130 is represented by the following chemical structure:

In certain embodiments, the sodium salt of Compound No. 1102130 is represented by the following chemical structure:

VIII. Certain Comparator Compositions

In certain embodiments, Compound No. 650528, which has been described in Moore, et al., Mol. Ther. Nucleic Acids, 2017, 7:200-210 (Moore, 2017) (“ASO-5”), WO 2018/089805, and McLoughlin et al., Ann. Neurol., 2018, 84:64-77 (McLoughlin, 2018) (each of which are incorporated herein by reference) was used as a comparator compound. Compound No. 650528 is a 5-8-5 MOE gapmer, having a sequence (from 5′ to 3′) GCATCTTTTCATACTGGC (SEQ ID NO: 2788), wherein each cytosine is a 5′-methylcytosine, each internucleoside linkage is either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage and the internucleoside linkage motif is s000sssssssssooss, wherein ‘s’ represents a phosphorothioate internucleoside linkage and ‘o’ represents a phosphodiester internucleoside linkage, and wherein each of nucleosides 1-5 and 14-18 comprise a 2′-MOE sugar moiety.

In certain embodiments, Compound No. 650668, which has been described in Moore, 2017 (“ASO-2”), WO 2018/089805, and McLoughlin, 2018 was used as a comparator compound. Compound No. 650668, is a 5-8-5 MOE gapmer, having a sequence (from 5′ to 3′) AGCCATTAATCTATACTG (SEQ ID NO: 2792), wherein each cytosine is a 5′-methylcytosine, each internucleoside linkage is either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage and the internucleoside linkage motif is s000sssssssssooss, wherein ‘s’ represents a phosphorothioate internucleoside linkage and ‘o’ represents a phosphodiester internucleoside linkage, and wherein each of nucleosides 1-5 and 14-18 comprise a 2′-MOE sugar moiety.

Compound No. 650528 and Compound No. 650668 were selected as comparator compounds because according to Moore, 2017 these compounds were “top ASO candidates” that were effective and tolerable. See, e.g., page 206, column 2, paragraph 1. In a follow up manuscript, Compound No. 650528 was further characterized as “ . . . the best ASO candidate . . . [f]rom this short-term safety and efficacy study . . . ” See, McLoughlin, 2018.

In certain embodiments, Compound No. 1244463 (“SH06”), which has been described in WO2013/138353 (incorporated by reference) is a comparator compound. Compound No. 1244463 is a 3-9-3 LNA gapmer, having a sequence (from 5′ to 3′) ATAGGTCCCGCTGCT (SEQ ID NO: 2793), and wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

In certain embodiments, Compound No. 1244464 (“SH10”), which has been described in WO2013/138353 is a comparator compound. Compound No. 1244464 is a 3-10-3 LNA gapmer, having a sequence (from 5′ to 3′) TGATAGGTCCCGCTGC (SEQ ID NO: 2794), and wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

In certain embodiments, Compound No. 1244465 (“SH13”), which has been described in WO2013/138353 is a comparator compound. Compound No. 1244465 is a 3-10-3 LNA gapmer, having a sequence (from 5′ to 3′) CTGATAGGTCCCGCTG (SEQ ID NO: 2795), and wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

In certain embodiments, Compound No. 1244466 (“SH16”), which has been described in WO2013/138353 is a comparator compound. Compound No. 1244466 is a 3-9-3 LNA gapmer, having a sequence (from 5′ to 3′) CTGATAGGTCCCGCT (SEQ ID NO: 2796), and wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

In certain embodiments, Compound No. 1244467 (“SH20”), which has been described in WO2013/138353 is a comparator compound. Compound No. 1244467 is a 2-9-3 LNA gapmer, having a sequence (from 5′ to 3′) CTGATAGGTCCCGC (SEQ ID NO: 2797), and wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

Compound No. 1244463, Compound No. 1244464, Compound No. 1244465, Compound No. 1244466, and Compound No. 1244467 were selected as comparator compounds because according to Example 2 of WO2013/138353 these compounds were selected for further study. Accordingly, these compounds were tested in further studies.

In certain embodiments, compounds described herein are superior relative to compounds described in Moore, 2017, WO 2018/089805, and WO2013/138353 because they demonstrate one or more improved properties, such as, potency and tolerability.

For example, as described herein, certain compounds Compound No. 1100673, Compound No. 1101657, and Compound No. 1102130 achieved an IC₅₀ in Example 7, hereinbelow, of 0.10 μM, 0.69 μM, and 0.47 μM, respectively, whereas comparator compound, Compound No. 650528 (“ASO-5”) achieved an IC₅₀ in Example 7, hereinbelow, of 2.03 μM and Compound No. 650668 (“ASO-2”) achieved an IC₅₀ in Example 2 of WO 2018/089805 of 1.7 μM. Therefore, certain compounds described herein are more potent than comparator compounds, Compound No. 650528 (“ASO-5”) and Compound No. 650668 (“ASO-2”) in this assay.

For example, as described herein, certain compounds Compound No. 1100673, Compound No. 1101657, and Compound No. 1102130 are more efficacious and potent than comparator compounds in vivo. See, e.g., Examples 4, 6, and 9, hereinbelow. For example, as provided in Examples 4 and 6, certain compounds Compound No. 1100673, Compound No. 1101657, and Compound No. 1102130 achieved an average expression level (% control) of 13%, 23%, and 27%, respectively, in spinal cord of transgenic mice whereas comparator compound, Compound No. 650528 (“ASO-5”) achieved an average expression level (% control) of 32% in spinal cord of transgenic mice. For example, as provided in Examples 4 and 6, certain compounds Compound No. 1100673, Compound No. 1101657, and Compound No. 1102130 achieved an average expression level (% control) of 13%, 23%, and 42%, respectively, in cortex of transgenic mice whereas comparator compound, Compound No. 650528 (“ASO-5”) achieved an average expression level (% control) of 43% in cortex of transgenic mice. For example, as provided in Examples 4 and 6, certain compounds Compound No. 1100673, Compound No. 1101657, and Compound No. 1102130 achieved an average expression level (% control) of 60%, 62%, and 68%, respectively, in cerebellum of transgenic mice whereas comparator compound, Compound No. 650528 (“ASO-5”) achieved an average expression level (% control) of 75% in cerebellum of transgenic mice. For example, as provided in Examples 4 and 6, certain compounds Compound No. 1100673, Compound No. 1101657, and Compound No. 1102130 achieved an average expression level (% control) of 14%, 26%, and 23%, respectively, in brain stem of transgenic mice whereas comparator compound, Compound No. 650528 (“ASO-5”) achieved an average expression level (% control) of 35% in brain stem of transgenic mice. Therefore, certain compounds described herein are more efficacious than comparator compound, Compound No. 650528 (“ASO-5”) in this assay. Specifically, certain compounds Compound No. 1100673, Compound No. 1101657, and Compound No. 1102130 are more efficacious than Compound No. 650528 (“ASO-5”) in every tissue tested in this assay.

For example, as described herein, certain compounds Compound No. 1100673, Compound No. 1101657, and Compound No. 1102130 achieved 3-hour FOB scores in mice of 1.00 (table 9) and 0.00 (table 20), 1.00 (table 9) and 0.00 (table 20), and 0.00 (table 8 and table 20), respectively, whereas each of comparator compounds Compound No. 1244463, Compound No. 1244464, Compound No. 1244465, Compound No. 1244466, and Compound No. 1244447 achieved 3-hour FOB scores in mice of 7.00 (table 26). Therefore, certain compounds described herein are more tolerable than comparator compounds Compound No. 1244463, Compound No. 1244464, Compound No. 1244465, Compound No. 1244466, and Compound No. 1244447 in this assay.

IX. Certain Hotspot Regions

1. Nucleobases 138-175 of SEQ ID NO: 1

In certain embodiments, nucleobases 138-175 of SEQ ID NO: 1 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 138-175 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 1060, 1061, 1062, 1063, 1064, and 1065 are complementary to nucleobases 138-175 of SEQ ID NO: 1.

In certain embodiments, modified oligonucleotides complementary to nucleobases 138-175 of SEQ ID NO: 1 achieve at least 79% reduction of ATXN3 RNA in vitro in the standard cell assay.

2. Nucleobases 392-436 of SEQ ID NO: 1

In certain embodiments, nucleobases 392-436 of SEQ ID NO: 1 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 392-436 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE gapmers. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 196, 197, 198,199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209 are complementary to nucleobases 392-436 of SEQ ID NO 1.

In certain embodiments, modified oligonucleotides complementary to nucleobases 392-436 of SEQ ID NO: 1 achieve an average of 77% reduction of ATXN3 RNA in vitro in the standard cell assay.

3. Nucleobases 1120-1146 of SEQ ID NO: 1

In certain embodiments, nucleobases 1120-1146 of SEQ ID NO: 1 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 1120-1146 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE gapmers. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 313, 314, 315, 316, and 317 are complementary to nucleobases 1120-1146 of SEQ ID NO: 1.

In certain embodiments, modified oligonucleotides complementary to nucleobases 1120-1146 of SEQ ID NO: 1 achieve at least 60% reduction of ATXN3 RNA in vitro in the standard cell assay.

4. Nucleobases 1823-1882 of SEQ ID NO:1

In certain embodiments, nucleobases 1823-1882 of SEQ ID NO: 1 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 1823-1882 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE gapmers. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 413-423 are complementary to nucleobases 1823-1882 of SEQ ID NO: 1.

In certain embodiments, modified oligonucleotides complementary to nucleobases 1823-1882 of SEQ ID NO: 1 achieve at least 60% reduction of ATXN3 RNA in vitro in the standard cell assay.

5. Nucleobases 3042-3098 of SEQ ID NO: 1

In certain embodiments, nucleobases 3042-3098 of SEQ ID NO: 1 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 3042-3098 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos:43, 44, 45, and 635-653 are complementary to nucleobases 3042-3098 of SEQ ID NO: 1.

In certain embodiments, modified oligonucleotides complementary to nucleobases 3042-3098 of SEQ ID NO: 1 achieve at least 64% reduction of ATXN3 RNA in vitro in the standard cell assay.

6. Nucleobases 3749-3801 of SEQ ID NO: 1

In certain embodiments, nucleobases 3749-3801 of SEQ ID NO: 1 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 3749-3801 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE gapmers. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 719-732 are complementary to nucleobases 3749-3801 of SEQ ID NO: 1.

In certain embodiments, modified oligonucleotides complementary to nucleobases 3749-3801 of SEQ ID NO: 1 achieve at least 52% reduction of ATXN3 RNA in vitro in the standard cell assay.

7. Nucleobases 5997-6021 of SEQ ID NO: 1

In certain embodiments, nucleobases 5997-6021 of SEQ ID NO: 1 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 5997-6021 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE gapmers. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 920-924 are complementary to nucleobases 5997-6021 of SEQ ID NO: 1.

In certain embodiments, modified oligonucleotides complementary to nucleobases 5997-6021 of SEQ ID NO: 2 achieve at least 75% reduction of ATXN3 RNA in vitro in the standard cell assay.

8. Nucleobases 19437-19476 of SEQ ID NO: 2

In certain embodiments, nucleobases 19437-19476 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 19437-19476 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 1671, 1672, 1673, and 1674 are complementary to nucleobases 19437-19476 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 19437-19476 of SEQ ID NO: 2 achieve at least 83% reduction of ATXN3 RNA in vitro in the standard cell assay.

9. Nucleobases 34440-34486 of SEQ ID NO: 2

In certain embodiments, nucleobases 34440-34486 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 34440-34486 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE gapmers. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 2233, 2234, 2235, 2236, and 2237 are complementary to nucleobases 34440-34486 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 34440-34486 of SEQ ID NO: 2 achieve at least 71% reduction of ATXN3 RNA in vitro in the standard cell assay.

10. Nucleobases 39883-39904 of SEQ ID NO: 2

In certain embodiments, nucleobases 39883-39904 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 39860-39904 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 2510, 2511, and 2512 are complementary to nucleobases 39883-39904 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 39883-39904 of SEQ ID NO: 2 achieve at least 89% reduction of ATXN3 RNA in vitro in the standard cell assay.

11. Nucleobases 6597-6618 of SEQ ID NO: 2

In certain embodiments, nucleobases 6597-6618 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 6597-6618 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE. In certain embodiments, the nucleosides of the modified oligonucleotides are linked by phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages.

The nucleobase sequences of SEQ ID Nos: 1226, 1227, and 1228 are complementary to nucleobases 6597-6618 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 6597-6618 of SEQ ID NO: 2 achieve at least 75% reduction of ATXN3 RNA in vitro in the standard cell assay.

Nonlimiting Disclosure and Incorporation by Reference

Each of the literature and patent publications listed herein is incorporated by reference in its entirety. While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references, GenBank accession numbers, and the like recited in the present application is incorporated herein by reference in its entirety.

Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH in place of one 2′-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of a uracil of RNA). Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases. By way of further example and without limitation, an oligomeric compound having the nucleobase sequence “ATCGATCG” encompasses any oligomeric compounds having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and oligomeric compounds having other modified nucleobases, such as “AT^(m)CGAUCG,” wherein ^(m)C indicates a cytosine base comprising a methyl group at the 5-position.

Certain compounds described herein (e.g., modified oligonucleotides) have one or more asymmetric center and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), as a or such as for sugar anomers, or as (D) or (L), such as for amino acids, etc. Compounds provided herein that are drawn or described as having certain stereoisomeric configurations include only the indicated compounds. Compounds provided herein that are drawn or described with undefined stereochemistry include all such possible isomers, including their stereorandom and optically pure forms, unless specified otherwise. Likewise, tautomeric forms of the compounds herein are also included unless otherwise indicated. Unless otherwise indicated, compounds described herein are intended to include corresponding salt forms.

The compounds described herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element. For example, compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the 41 hydrogen atoms. Isotopic substitutions encompassed by the compounds herein include but are not limited to: ^(2H) or ³H in place of 41, ¹³C or ^(m)C in place of ¹²C, ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in place of ¹⁶O, and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S. In certain embodiments, non-radioactive isotopic substitutions may impart new properties on the oligomeric compound that are beneficial for use as a therapeutic or research tool. In certain embodiments, radioactive isotopic substitutions may make the compound suitable for research or diagnostic purposes such as imaging.

EXAMPLES

The following examples illustrate certain embodiments of the present disclosure and are not limiting. Moreover, where specific embodiments are provided, the inventors have contemplated generic application of those specific embodiments. For example, disclosure of an oligonucleotide having a particular motif provides reasonable support for additional oligonucleotides having the same or similar motif. And, for example, where a particular high-affinity modification appears at a particular position, other high-affinity modifications at the same position are considered suitable, unless otherwise indicated.

Example 1: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human ATXN3 In Vitro, Single Dose

Modified oligonucleotides complementary to a human ATXN3 nucleic acid were designed and tested for their effect on ATXN3 RNA in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions.

Cultured A431 cells at a density of 10,000 cells per well were transfected by free uptake with 4,000 nM concentration of modified oligonucleotide or no modified oligonucleotide for untreated controls. After approximately 24 hours, RNA was isolated from the cells and ATXN3 RNA levels were measured by quantitative real-time PCR Human primer probe set RTS38920 (forward sequence CTATCAGGACAGAGTTCACATCC, designated herein as SEQ ID NO: 6; reverse sequence GTTTCTAAAGACATGGTCACAGC, designated herein as SEQ ID NO: 7; probe sequence AAAGGCCAGCCACCAGTTCAGG, designated herein as SEQ ID: 8) was used to measure RNA levels. ATXN3 RNA levels were adjusted according to total RNA content, as measured by RiboGreen®. Results are presented in the table below as percent ATXN3 RNA levels relative to untreated control cells. The modified oligonucleotides marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of oligonucleotides targeting the amplicon region.

The modified oligonucleotides in the tables below are 5-10-5 MOE gapmers. The gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2′-deoxynucleosides and is flanked by wing segments on both the 5′ end and on the 3′ end comprising five 2′-MOE nucleosides each. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-deoxyribose sugar and ‘e’ represents a 2′-MOE modified sugar. All cytosine residues throughout each gapmer are 5-methyl cytosines. The internucleoside linkages are mixed phosphodiester and phosphorothioate linkages. The internucleoside linkage motif for the gapmers is (from 5′ to 3′): s000sssssssssssooss; wherein ‘o’ represents a phosphodiester internucleoside linkage and ‘s’ represents a phosphorothioate internucleoside linkage. “Start Site” indicates the 5′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence. “Stop Site” indicates the 3′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence.

Each modified oligonucleotide listed in the tables below is complementary to human ATXN3 nucleic acid sequences SEQ ID No: 1, SEQ ID No: 2, SEQ ID No: 3, SEQ ID No: 4, or SEQ ID No: 5, as indicated. ‘N/A’ indicates that the modified oligonucleotide is not complementary to that particular nucleic acid sequence with 100% complementarity. As shown below, modified oligonucleotides complementary to human ATXN3 reduced the amount of human ATXN3 RNA.

TABLE 1 Percent control of human ATXN3 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID No: ID No: ID No: ID No: ATXN3 SEQ Compound 1 Start 1 Stop 2 Start 2 Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 1100357   15   34  3394  3413 ACCACCCCCTCCAGCTCCGC  88  15 1100359   17   36  3396  3415 GAACCACCCCCTCCAGCTCC  83  16 1100393  383  402 N/A N/A TGATCTTTCATTTATAGGAT  86  17 1100395  385  404 N/A N/A AATGATCTTTCATTTATAGG  74  18 1100429  458  477 21185 21204 GAGAGAATTCAAGTTAAACC  25  19 1100431  470  489 21197 21216 TGGACCCGTCAAGAGAGAAT  35  20 1100465  638  657 26836 26855 TAATTCTTCTCCAATAAGTT 101  21 1100467  641  660 26839 26858 TGCTAATTCTTCTCCAATAA  92  22 1100501  812  831 27669 27688 CTGAATAGCCCTGCGGAGAT  82  23 1100503  819  838 27676 27695 TACTTAGCTGAATAGCCCTG  99  24 1100573 1222 1241 45748 45767 TGACACATTACCAAAGTGGA  52  25 1100575 1225 1244 45751 45770 CTTTGACACATTACCAAAGT  94  26 1100609 1562 1581 46088 46107 TGGTTAATAAGAAATGAAAG  79  27 1100611 1566 1585 46092 46111 AATTTGGTTAATAAGAAATG  87  28 1100645 1758 1777 46284 46303 AAAAGATTACCATCTTTCAA  64  29 1100647 1760 1779 46286 46305 AGAAAAGATTACCATCTTTC  84  30 1100681 2005 2024 46531 46550 TCCTAGTTTTCTCAATTGGA  94  31 1100683 2007 2026 46533 46552 TCTCCTAGTTTTCTCAATTG  57  32 1100717 2211 2230 46737 46756 CAAGCTATACCTACTAAAAG  76  33 1100719 2213 2232 46739 46758 GACAAGCTATACCTACTAAA  22  34 1100753 2319 2338 46845 46864 CCATTGTTCTTAAGCTATCT  27  35 1100755 2348 2367 46874 46893 ATTTATAGATCCACTAAGTA  85  36 1100789 2540 2559 47066 47085 AGCTTATGAACAATTCAACA  31  37 1100791 2545 2564 47071 47090 ATTTTAGCTTATGAACAATT  78  38 1100825 2659 2678 47185 47204 TTAGCAATAAATCCTAGATC  59  39 1100827 2661 2680 47187 47206 AGTTAGCAATAAATCCTAGA  39  40 1100861 2896 2915 47422 47441 GAGGGAGTAGTACTAAACTC  57  41 1100863 2911 2930 47437 47456 AGCTTTTTAAATCTTGAGGG  21  42 1100897 3042 3061 47568 47587 GCTCATCAATTCAAGTGTAT  31  43 1100899 3044 3063 47570 47589 TAGCTCATCAATTCAAGTGT  31  44 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7  45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7  45 1100934 3539 3558 48065 48084 AAACACATTCAAACGCATCC  69  46 1100936 3541 3560 48067 48086 ACAAACACATTCAAACGCAT  65  47 1100970 3665 3684 48191 48210 TGGCCAATCAATTAAGAAAT  93  48 1100972 3671 3690 48197 48216 TCATACTGGCCAATCAATTA  68  49 1101006 3792 3811 48318 48337 TTAGTTGTTCCTGACTTTCT  59  50 1101008 3803 3822 48329 48348 TTCTTGTGAATTTAGTTGTT  43  51 1101042 3918 3937 48444 48463 GTAATACAAATTATACATTA 104  52 1101044 3921 3940 48447 48466 CCAGTAATACAAATTATACA  53  53 1101078 4010 4029 48536 48555 ACTCATTAAATCCATGACAT  53  54 1101080 4012 4031 48538 48557 TTACTCATTAAATCCATGAC  62  55 1101114 4123 4142 48649 48668 CAGCCTTTTCAAACAGTTTA  39  56 1101116 4125 4144 48651 48670 AGCAGCCTTTTCAAACAGTT  31  57 1101150 4402 4421 48928 48947 TAGTATCAAAAATTCAGACA  90  58 1101152 4757 4776 49283 49302 GTTTTAAGAATTTAGTAGCT  71  59 1101186 5957 5976 50483 50502 TCGATACAACAAACAATTCA  62  60 1101188 5959 5978 50485 50504 ACTCGATACAACAAACAATT  80  61 1101222 6143 6162 50669 50688 GACTAAAAAAATACAAAGCC  78  62 1101224 6200 6219 50726 50745 TCAATAATCTTCACTCATGA  87  63 1101258 6539 6558 51065 51084 ACATTTAAAAATGTATGTTT  83  64 1101260 6551 6570 51077 51096 AATTAGATAATCACATTTAA 102  65 1101294 6660 6679 51186 51205 GCCAAACAACAATGCTTTTT  58  66 1101296 6662 6681 51188 51207 TGGCCAAACAACAATGCTTT  93  67 1101330 6882 6901 51408 51427 ATTTAATAATCTTTGATATT  76  68 1101332 6890 6909 51416 51435 TTATCTTTATTTAATAATCT  87  69 1101366  207  226 13276 13295 CTCCTCCTTCTGCCATTCTC  57  70 1101368  212  231 13281 13300 AGTAACTCCTCCTTCTGCCA  43  71 1101438 N/A N/A 53335 53354 CTACCCTAATACAAGAGACT 108  72 1101440 N/A N/A 53468 53487 AAACCCTACAAATACTGAAT 102  73 1101582 N/A N/A  4112  4131 AACCAAACCCAAACATCCCG  59  74 1101584 N/A N/A  4114  4133 GAAACCAAACCCAAACATCC  87  75 1101618 N/A N/A  4906  4925 TCAGCCTATTTCAAAAGTTT 100  76 1101620 N/A N/A  4954  4973 AAAATTAGTGACAACTATAC  78  77 1101654 N/A N/A  6579  6598 AAACTCAAAGCCATCTCTTT  80  78 1101656 N/A N/A  6594  6613 CCATATATATCTCAGAAACT  84  79 1101690 N/A N/A  7113  7132 AAGTCATTTATACAGAATTT  69  80 1101692 N/A N/A  7146  7165 CAGAGGTTTCAAAACCTGTG  73  81 1101726 N/A N/A  8509  8528 TTATCTCAAACTATCCCCAG  91  82 1101728 N/A N/A  8512  8531 CCCTTATCTCAAACTATCCC  99  83 1101762 N/A N/A  9034  9053 AGTTTACAAACTATGGTCAC  79  84 1101764 N/A N/A  9037  9056 TGGAGTTTACAAACTATGGT  37  85 1101798 N/A N/A  9800  9819 TAACCAATAATAACTAATAA  87  86 1101800 N/A N/A  9807  9826 ATTGGTATAACCAATAATAA 110  87 1101834 N/A N/A 11212 11231 CTGTCCCAAACAACCCTGGA  88  88 1101836 N/A N/A 11217 11236 CAGAACTGTCCCAAACAACC  85  89 1101870 N/A N/A 12035 12054 TTACATGATCAAAAATTTAA  85  90 1101872 N/A N/A 12070 12089 TTTATTTTACAAATCTACCA  88  91 1101906 N/A N/A 14226 14245 ACGGTGAAACCCCACTATCT  79  92 1101908 N/A N/A 14332 14351 CTATATAAAAATCTAGTACT 102  93 1101942 N/A N/A 15045 15064 ATAAACAAAGATATCTGCAG  98  94 1101944 N/A N/A 15201 15220 AGCAAGGCACAAATAGGAAA  95  95 1101978 N/A N/A 15710 15729 ATATATCACTAAATCCATAA  75  96 1101980 N/A N/A 15713 15732 TAGATATATCACTAAATCCA  77  97 1102014 N/A N/A 16642 16661 ATTAACTTGAAATATTGAAT 110  98 1102016 N/A N/A 16674 16693 ATCTTTCATTTCTAAAAAAG  83  99 1102050 N/A N/A 17448 17467 TGACACTATTTCAGGCTTTG   7 100 1102052 N/A N/A 17466 17485 GAATGCTTTATTCATGCTTG  31 101 1102086 N/A N/A 18832 18851 TAAGAAAGAACCAACTTAGG  85 102 1102088 N/A N/A 18841 18860 GAAGAACTTTAAGAAAGAAC  83 103 1102122 N/A N/A 19392 19411 TAGTGAAAAATATAGTTTTA 112 104 1102124 N/A N/A 19394 19413 TATAGTGAAAAATATAGTTT  90 105 1102158 N/A N/A 19863 19882 ACATTTTTTTAAAAGAGATG 108 106 1102160 N/A N/A 19882 19901 TCACATATAACATATAAACA  75 107 1102194 N/A N/A 20985 21004 CTGCAGATTTATCACTATTA  71 108 1102196 N/A N/A 21009 21028 GATCTTAAAAACTACAAGAG  69 109 1102230 N/A N/A 22011 22030 CGAGTCAGATCCTAAAATCA  77 110 1102232 N/A N/A 22184 22203 GGTGGTAGTTAAAGAGTAAT  74 111 1102266 N/A N/A 22927 22946 TAACGGAAAGCCACAAGGAA 103 112 1102268 N/A N/A 22966 22985 GAACATAATTTTAATTGCTT  65 113 1102302 N/A N/A 23986 24005 GTATCTAAAATCAAAGAATT  81 114 1102304 N/A N/A 23989 24008 CAAGTATCTAAAATCAAAGA  89 115 1102338 N/A N/A 25018 25037 ATGGAAAACCTCAAAATAGT  81 116 1102340 N/A N/A 25428 25447 TTTAAGTTTCTCTATCATTA  87 117 1102374 N/A N/A 25709 25728 GTGTGCAATAACTAGTAACA  33 118 1102376 N/A N/A 25807 25826 TACATTACCCTTCATATATA  77 119 1102410 N/A N/A 26869 26888 GCCTCATTTTTACCTTTGCT  64 120 1102412 N/A N/A 26871 26890 AGGCCTCATTTTTACCTTTG 104 121 1102446 N/A N/A 27823 27842 AAGGGAAAGCCCACTATATA  90 122 1102448 N/A N/A 27834 27853 TAAGAAATCTAAAGGGAAAG  93 123 1102482 N/A N/A 28191 28210 TTAACATTTTTCTTTGCCTA  76 124 1102484 N/A N/A 28228 28247 ACTTCAAACTTTTAATTAAG  86 125 1102518 N/A N/A 28890 28909 AATCACTGTATTTACCAATT  99 126 1102520 N/A N/A 28901 28920 CAACAAAAACCAATCACTGT  98 127 1102554 N/A N/A 29810 29829 GAGTTGATCCAGATTTATGG  41 128 1102556 N/A N/A 29863 29882 GGAATTCCTATTTAGCAAGC  78 129 1102590 N/A N/A 30581 30600 TAGAAATATCTCACATTAAG  70 130 1102592 N/A N/A 30586 30605 AAGACTAGAAATATCTCACA  56 131 1102626 N/A N/A 31259 31278 TGATTATTATTTTATGACAA  75 132 1102628 N/A N/A 31312 31331 TATTTTTTACATTAACTAGA  79 133 1102662 N/A N/A 33021 33040 TCTGAAATAAACATGGTGAA  72 134 1102664 N/A N/A 33385 33404 TTATAGTTTCTCTATGATGT  69 135 1102698 N/A N/A 34137 34156 AAGAAGTTAGTTCTTAACTC  72 136 1102700 N/A N/A 34168 34187 TGAATGCAAGCCATTGTTAA  52 137 1102734 N/A N/A 34497 34516 GCATGAAAACTATGATTACT  18 138 1102736 N/A N/A 34499 34518 ATGCATGAAAACTATGATTA  69 139 1102770 N/A N/A 35322 35341 TTATGTAAACCCCTAATTTC 109 140 1102772 N/A N/A 35438 35457 TAATATCCTCATTACCCATT  89 141 1102806 N/A N/A 36969 36988 TTAGCAAATCCTGATGCTGC  72 142 1102808 N/A N/A 36980 36999 GTATCCTCCCATTAGCAAAT  35 143 1102842 N/A N/A 37709 37728 TATTATTCCCAAATGGTTCA  64 144 1102844 N/A N/A 37730 37749 TAATGGAAAATCATATCTGC  56 145 1102878 N/A N/A 38268 38287 CCTTTGATCAGATAAAGCAT  62 146 1102880 N/A N/A 38289 38308 GAAAGTCACCAAAAATAAGT  75 147 1102914 N/A N/A 38842 38861 ACATTGTTTCACGAATCAAA  65 148 1102916 N/A N/A 38853 38872 ATAAGGAAAATACATTGTTT 111 149 1100537* 1088 1107 45614 45633 CATGGTCACAGCTGCCTGAA  31 150 1100539* 1090 1109 45616 45635 GACATGGTCACAGCTGCCTG  16 151 1102950* N/A N/A 39345 39364 TGAAGTTTAAATTATTATGT  79 152 1102952* N/A N/A 39361 39380 ACTGTACAAATTACTGTGAA  67 153 1102986* N/A N/A 40095 40114 TTATTTCTTCATTAAAGCCA  50 154 1102988* N/A N/A 40202 40221 CAAAAAAATGCCAAACTGTT  96 155 1103022* N/A N/A 42830 42849 GCTGTCATTCAAATTGCTTA  60 156 1103024* N/A N/A 42892 42911 ACTAGAAAAAATGTTGTATG  74 157 1103058* N/A N/A 44033 44052 TAAAATAGTTTTCTAAATGT 108 158 1103060* N/A N/A 44071 44090 AATATTAGCCAAAGAGGCAT 106 159 1103094* N/A N/A 45111 45130 TGTAAAGATATTTAAGAGAG  75 160 1103096* N/A N/A 45130 45149 CTGTCAATTCAAAGGAAGTT  51 161

TABLE 2 Percent control of human ATXN3 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID No: ID No: ID No: ID No: ATXN3 SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO 1100358   16   35  3395  3414 AACCACCCCCTCCAGCTCCG  85  162 1100360   18   37  3397  3416 CGAACCACCCCCTCCAGCTC 111  163 1100361   19   38  3398  3417 CCGAACCACCCCCTCCAGCT 103  164 1100362   44   63  3423  3442 TTGTCTGGAGCCAACGGCCC  64  165 1100363   56   75  3435  3454 CTCCATGTTTATTTGTCTGG  97  166 1100364   57   76  3436  3455 ACTCCATGTTTATTTGTCTG  86  167 1100365   63   82  3442  3461 AGATGGACTCCATGTTTATT  89  168 1100368  312  331 16178 16197 CCCAAACTTTCAAGGCATTG  79  169 1100369  313  332 16179 16198 CCCCAAACTTTCAAGGCATT  30  170 1100370  314  333 16180 16199 ACCCCAAACTTTCAAGGCAT  36  171 1100371  315  334 16181 16200 AACCCCAAACTTTCAAGGCA  50  172 1100372  316  335 16182 16201 AAACCCCAAACTTTCAAGGC  45  173 1100373  319  338 16185 16204 TCTAAACCCCAAACTTTCAA  57  174 1100374  320  339 16186 16205 TTCTAAACCCCAAACTTTCA  92  175 1100375  321  340 16187 16206 GTTCTAAACCCCAAACTTTC  48  176 1100376  322  341 16188 16207 AGTTCTAAACCCCAAACTTT  63  177 1100377  323  342 16189 16208 TAGTTCTAAACCCCAAACTT  81  178 1100378  324  343 16190 16209 TTAGTTCTAAACCCCAAACT  58  179 1100379  326  345 16192 16211 GATTAGTTCTAAACCCCAAA  15  180 1100380  327  346 16193 16212 GGATTAGTTCTAAACCCCAA  25  181 1100381  328  347 16194 16213 AGGATTAGTTCTAAACCCCA  23  182 1100382  330  349 16196 16215 ACAGGATTAGTTCTAAACCC  24  183 1100383  338  357 16204 16223 ACTGTTGAACAGGATTAGTT  64  184 1100384  356  375 16222 16241 GAGCCTCTGATACTCTGGAC  23  185 1100385  357  376 16223 16242 TGAGCCTCTGATACTCTGGA  51  186 1100386  359  378 16225 16244 CCTGAGCCTCTGATACTCTG  88  187 1100387  363  382 16229 16248 CGATCCTGAGCCTCTGATAC  41  188 1100388  368  387 16234 16253 AGGATCGATCCTGAGCCTCT  78  189 1100389  369  388 16235 16254 TAGGATCGATCCTGAGCCTC  91  190 1100390  371  390 N/A N/A TATAGGATCGATCCTGAGCC  60  191 1100391  372  391 N/A N/A TTATAGGATCGATCCTGAGC  71  192 1100392  381  400 N/A N/A ATCTTTCATTTATAGGATCG  59  193 1100394  384  403 N/A N/A ATGATCTTTCATTTATAGGA  92  194 1100396  391  410 16684 16703 CATATAAATGATCTTTCATT  79  195 1100397  392  411 16685 16704 GCATATAAATGATCTTTCAT   7  196 1100398  393  412 16686 16705 TGCATATAAATGATCTTTCA  12  197 1100399  394  413 16687 16706 TTGCATATAAATGATCTTTC  13  198 1100400  395  414 16688 16707 ATTGCATATAAATGATCTTT  31  199 1100401  397  416 16690 16709 TAATTGCATATAAATGATCT  68  200 1100402  403  422 16696 16715 TCCTTATAATTGCATATAAA  35  201 1100403  406  425 16699 16718 TGTTCCTTATAATTGCATAT  15  202 1100404  407  426 16700 16719 GTGTTCCTTATAATTGCATA  76  203 1100405  408  427 16701 16720 AGTGTTCCTTATAATTGCAT   7  204 1100406  409  428 16702 16721 CAGTGTTCCTTATAATTGCA   7  205 1100407  410  429 16703 16722 CCAGTGTTCCTTATAATTGC  10  206 1100408  411  430 16704 16723 ACCAGTGTTCCTTATAATTG   7  207 1100409  412  431 16705 16724 AACCAGTGTTCCTTATAATT  12  208 1100410  417  436 16710 16729 CTGTAAACCAGTGTTCCTTA  19  209 1100411  420  439 16713 16732 TAACTGTAAACCAGTGTTCC  80  210 1100412  421  440 16714 16733 CTAACTGTAAACCAGTGTTC  32  211 1100413  427  446 16720 16739 AATTTTCTAACTGTAAACCA  86  212 1100414  430  449 16723 16742 CCTAATTTTCTAACTGTAAA  79  213 1100415  431  450 16724 16743 TCCTAATTTTCTAACTGTAA  81  214 1100416  432  451 16725 16744 TTCCTAATTTTCTAACTGTA  71  215 1100417  433  452 16726 16745 TTTCCTAATTTTCTAACTGT  68  216 1100418  435  454 16728 16747 GTTTTCCTAATTTTCTAACT  75  217 1100419  438  457 N/A N/A ACTGTTTTCCTAATTTTCTA  56  218 1100420  440  459 N/A N/A CCACTGTTTTCCTAATTTTC  46  219 1100421  441  460 N/A N/A ACCACTGTTTTCCTAATTTT  38  220 1100422  442  461 N/A N/A AACCACTGTTTTCCTAATTT  48  221 1100423  447  466 N/A N/A AGTTAAACCACTGTTTTCCT  49  222 1100424  448  467 N/A N/A AAGTTAAACCACTGTTTTCC  58  223 1100425  450  469 N/A N/A TCAAGTTAAACCACTGTTTT  60  224 1100426  451  470 N/A N/A TTCAAGTTAAACCACTGTTT  60  225 1100427  453  472 N/A N/A AATTCAAGTTAAACCACTGT  66  226 1100428  456  475 21183 21202 GAGAATTCAAGTTAAACCAC  37  227 1100430  463  482 21190 21209 GTCAAGAGAGAATTCAAGTT  22  228 1100432  472  491 21199 21218 TCTGGACCCGTCAAGAGAGA  40  229 1100433  493  512 21220 21239 AGATATGTATCTGATATTAA  47  230 1100434  500  519 21227 21246 AAGTGCAAGATATGTATCTG  20  231 1100435  501  520 21228 21247 AAAGTGCAAGATATGTATCT  34  232 1100436  502  521 21229 21248 AAAAGTGCAAGATATGTATC  51  233 1100437  507  526 21234 21253 CCAAGAAAAGTGCAAGATAT  45  234 1100438  511  530 21238 21257 TGAGCCAAGAAAAGTGCAAG  77  235 1100439  512  531 21239 21258 TTGAGCCAAGAAAAGTGCAA  78  236 1100440  515  534 21242 21261 TAATTGAGCCAAGAAAAGTG  75  237 1100441  517  536 21244 21263 TGTAATTGAGCCAAGAAAAG  77  238 1100442  522  541 21249 21268 CCTGTTGTAATTGAGCCAAG  42  239 1100443  531  550 N/A N/A AATAACCTTCCTGTTGTAAT  61  240 1100444  532  551 N/A N/A GAATAACCTTCCTGTTGTAA  54  241 1100445  533  552 N/A N/A AGAATAACCTTCCTGTTGTA  47  242 1100446  534  553 N/A N/A TAGAATAACCTTCCTGTTGT  51  243 1100447  535  554 N/A N/A ATAGAATAACCTTCCTGTTG  62  244 1100448  536  555 N/A N/A TATAGAATAACCTTCCTGTT  64  245 1100449  537  556 N/A N/A ATATAGAATAACCTTCCTGT  80  246 1100450  539  558 N/A N/A AAATATAGAATAACCTTCCT  73  247 1100451  540  559 N/A N/A CAAATATAGAATAACCTTCC  73  248 1100452  541  560 N/A N/A ACAAATATAGAATAACCTTC  76  249 1100453  546  565 26744 26763 TAACGACAAATATAGAATAA  93  250 1100454  558  577 26756 26775 GCAGATCACCCTTAACGACA  26  251 1100455  561  580 26759 26778 CTGGCAGATCACCCTTAACG  35  252 1100456  563  582 26761 26780 ATCTGGCAGATCACCCTTAA  54  253 1100457  564  583 26762 26781 AATCTGGCAGATCACCCTTA  75  254 1100458  565  584 26763 26782 CAATCTGGCAGATCACCCTT  49  255 1100459  566  585 26764 26783 GCAATCTGGCAGATCACCCT  48  256 1100460  567  586 26765 26784 CGCAATCTGGCAGATCACCC  60  257 1100461  568  587 26766 26785 TCGCAATCTGGCAGATCACC  48  258 1100462  569  588 26767 26786 TTCGCAATCTGGCAGATCAC  87  259 1100463  571  590 26769 26788 GCTTCGCAATCTGGCAGATC  67  260 1100464  635  654 26833 26852 TTCTTCTCCAATAAGTTTTG  81  261 1100466  639  658 26837 26856 CTAATTCTTCTCCAATAAGT  96  262 1100468  642  661 26840 26859 GTGCTAATTCTTCTCCAATA  23  263 1100469  644  663 26842 26861 TTGTGCTAATTCTTCTCCAA  72  264 1100470  645  664 26843 26862 GTTGTGCTAATTCTTCTCCA  34  265 1100471  675  694 N/A N/A GGTCTGTTTTATGGACTCTT  60  266 1100472  677  696 27534 27553 CAGGTCTGTTTTATGGACTC  86  267 1100473  678  697 27535 27554 CCAGGTCTGTTTTATGGACT  69  268 1100474  700  719 27557 27576 TCATTTGCTTCTAACACTCG  87  269 1100475  705  724 27562 27581 AGCCATCATTTGCTTCTAAC  19  270 1100476  711  730 27568 27587 TTCCTGAGCCATCATTTGCT  80  271 1100477  712  731 27569 27588 ATTCCTGAGCCATCATTTGC  52  272 1100478  713  732 27570 27589 CATTCCTGAGCCATCATTTG  56  273 1100479  718  737 27575 27594 TCTAACATTCCTGAGCCATC  18  274 1100480  739  758 27596 27615 TGCAAATCCTCCTCATCTTC  42  275 1100481  740  759 27597 27616 CTGCAAATCCTCCTCATCTT  53  276 1100482  741  760 27598 27617 TCTGCAAATCCTCCTCATCT  53  277 1100483  742  761 27599 27618 CTCTGCAAATCCTCCTCATC  64  278 1100484  743  762 27600 27619 CCTCTGCAAATCCTCCTCAT  46  279 1100485  745  764 27602 27621 GCCCTCTGCAAATCCTCCTC  58  280 1100486  752  771 27609 27628 TGCCAGAGCCCTCTGCAAAT  68  281 1100487  754  773 27611 27630 AGTGCCAGAGCCCTCTGCAA  64  282 1100488  760  779 27617 27636 CGACTTAGTGCCAGAGCCCT  86  283 1100489  762  781 27619 27638 GGCGACTTAGTGCCAGAGCC  83  284 1100490  767  786 27624 27643 TTCTTGGCGACTTAGTGCCA  59  285 1100491  776  795 27633 27652 CATGTCAATTTCTTGGCGAC  83  286 1100492  777  796 27634 27653 CCATGTCAATTTCTTGGCGA  72  287 1100493  786  805 27643 27662 CCTCATCTTCCATGTCAATT  66  288 1100494  788  807 27645 27664 TTCCTCATCTTCCATGTCAA  52  289 1100495  789  808 27646 27665 CTTCCTCATCTTCCATGTCA  47  290 1100496  792  811 27649 27668 CTGCTTCCTCATCTTCCATG  28  291 1100497  793  812 27650 27669 TCTGCTTCCTCATCTTCCAT  33  292 1100498  794  813 27651 27670 ATCTGCTTCCTCATCTTCCA  37  293 1100499  795  814 27652 27671 GATCTGCTTCCTCATCTTCC  43  294 1100500  796  815 27653 27672 AGATCTGCTTCCTCATCTTC  45  295 1100502  814  833 27671 27690 AGCTGAATAGCCCTGCGGAG  68  296 1100504  827  846 27684 27703 ACCTTGCATACTTAGCTGAA  77  297 1100505  833  852 N/A N/A GGAACTACCTTGCATACTTA  20  298 1100506  836  855 N/A N/A TCTGGAACTACCTTGCATAC  47  299 1100507  838  857 N/A N/A TTTCTGGAACTACCTTGCAT  69  300 1100508  875  894 28970 28989 ATTTGTACCTGATGTCTGTG  30  301 1100509  877  896 28972 28991 AGATTTGTACCTGATGTCTG  50  302 1100510  883  902 28978 28997 GAAGTAAGATTTGTACCTGA  41  303 1100511  885  904 28980 28999 CTGAAGTAAGATTTGTACCT  91  304 1100512  886  905 28981 29000 TCTGAAGTAAGATTTGTACC  91  305 1100513  904  923 28999 29018 CGTCTCTTCCGAAGCTCTTC  69  306 1100514  926  945 N/A N/A CTGTTTTTCAAAGTAGGCTT  41  307 1100515  927  946 N/A N/A GCTGTTTTTCAAAGTAGGCT  67  308 1100516  928  947 N/A N/A TGCTGTTTTTCAAAGTAGGC  43  309 1100517  929  948 N/A N/A CTGCTGTTTTTCAAAGTAGG  81  310 1100518  930  949 N/A N/A GCTGCTGTTTTTCAAAGTAG  65  311 1100519  931  950 N/A N/A TGCTGCTGTTTTTCAAAGTA  44  312 1100557 1120 1139 45646 45665 GTTTTCAAATCATTTCTGAC  19  313 1100558 1121 1140 45647 45666 TGTTTTCAAATCATTTCTGA  40  314 1100559 1122 1141 45648 45667 CTGTTTTCAAATCATTTCTG  12  315 1100560 1126 1145 45652 45671 CCTTCTGTTTTCAAATCATT  20  316 1100561 1127 1146 45653 45672 TCCTTCTGTTTTCAAATCAT  20  317 1100562 1143 1162 45669 45688 AAAGGTATTATTTTTTTCCT  39  318 1100563 1144 1163 45670 45689 TAAAGGTATTATTTTTTTCC  29  319 1100564 1145 1164 45671 45690 TTAAAGGTATTATTTTTTTC 122  320 1100565 1167 1186 45693 45712 GTATGAATATCTAAATTATT  80  321 1100566 1172 1191 45698 45717 GGAAAGTATGAATATCTAAA   3  322 1100567 1176 1195 45702 45721 TGTTGGAAAGTATGAATATC  19  323 1100568 1209 1228 45735 45754 AAGTGGACCCTATGCTGTAA  20  324 1100569 1210 1229 45736 45755 AAAGTGGACCCTATGCTGTA  50  325 1100570 1211 1230 45737 45756 CAAAGTGGACCCTATGCTGT  85  326 1100571 1220 1239 45746 45765 ACACATTACCAAAGTGGACC  14  327 1100572 1221 1240 45747 45766 GACACATTACCAAAGTGGAC  13  328 1100574 1223 1242 45749 45768 TTGACACATTACCAAAGTGG  25  329 1100576 1226 1245 45752 45771 TCTTTGACACATTACCAAAG  64  330 1100577 1227 1246 45753 45772 CTCTTTGACACATTACCAAA  35  331 1100578 1228 1247 45754 45773 TCTCTTTGACACATTACCAA  54  332 1100579 1230 1249 45756 45775 CATCTCTTTGACACATTACC  34  333 1100580 1232 1251 45758 45777 CTCATCTCTTTGACACATTA  16  334 1100581 1235 1254 45761 45780 TTCCTCATCTCTTTGACACA  33  335 1100582 1240 1259 45766 45785 CTTATTTCCTCATCTCTTTG  33  336 1100583 1243 1262 45769 45788 AGTCTTATTTCCTCATCTCT  17  337 1100584 1244 1263 45770 45789 AAGTCTTATTTCCTCATCTC  81  338 1100585 1245 1264 45771 45790 AAAGTCTTATTTCCTCATCT  10  339 1100586 1246 1265 45772 45791 AAAAGTCTTATTTCCTCATC  31  340 1100587 1307 1326 45833 45852 TTATTTAGTCCTACAACCGA  62  341 1100588 1311 1330 45837 45856 ATCATTATTTAGTCCTACAA  30  342 1100589 1314 1333 45840 45859 AAGATCATTATTTAGTCCTA  17  343 1100590 1317 1336 45843 45862 TGGAAGATCATTATTTAGTC   6  344 1100591 1318 1337 45844 45863 TTGGAAGATCATTATTTAGT  11  345 1100592 1319 1338 45845 45864 TTTGGAAGATCATTATTTAG  23  346 1100593 1321 1340 45847 45866 TATTTGGAAGATCATTATTT  66  347 1100594 1322 1341 45848 45867 ATATTTGGAAGATCATTATT  84  348 1100595 1331 1350 45857 45876 CTTTGGCTAATATTTGGAAG  37  349 1100596 1332 1351 45858 45877 TCTTTGGCTAATATTTGGAA  43  350 1100597 1333 1352 45859 45878 CTCTTTGGCTAATATTTGGA  12  351 1100598 1344 1363 45870 45889 TTGCTGAATGCCTCTTTGGC  33  352 1100599 1400 1419 45926 45945 TTGCACACTCAAAAAAGAAA  72  353 1100600 1402 1421 45928 45947 TATTGCACACTCAAAAAAGA 105  354 1100601 1403 1422 45929 45948 ATATTGCACACTCAAAAAAG  70  355 1100602 1441 1460 45967 45986 AAGATCCAAGAAAAATGCCC  78  356 1100603 1447 1466 45973 45992 TGCAAAAAGATCCAAGAAAA 105  357 1100604 1448 1467 45974 45993 CTGCAAAAAGATCCAAGAAA  65  358 1100605 1449 1468 45975 45994 TCTGCAAAAAGATCCAAGAA  68  359 1100606 1498 1517 46024 46043 AGAAAACAAACTATATGGAA  87  360 1100607 1550 1569 46076 46095 AATGAAAGCCACTATTACAT  74  361 1100608 1552 1571 46078 46097 GAAATGAAAGCCACTATTAC  59  362 1100610 1565 1584 46091 46110 ATTTGGTTAATAAGAAATGA 103  363 1100612 1567 1586 46093 46112 TAATTTGGTTAATAAGAAAT  87  364 1100613 1575 1594 46101 46120 TGAAAGGTTAATTTGGTTAA  93  365 1100614 1576 1595 46102 46121 CTGAAAGGTTAATTTGGTTA  70  366 1100615 1583 1602 46109 46128 TACTTTCCTGAAAGGTTAAT 109  367 1100616 1586 1605 46112 46131 AGATACTTTCCTGAAAGGTT  72  368 1100617 1587 1606 46113 46132 GAGATACTTTCCTGAAAGGT  97  369 1100618 1588 1607 46114 46133 AGAGATACTTTCCTGAAAGG 107  370 1100619 1611 1630 46137 46156 ACTATTATCAACATCAGGAA  90  371 1100620 1619 1638 46145 46164 GAACCATTACTATTATCAAC 120  372 1100621 1620 1639 46146 46165 AGAACCATTACTATTATCAA  31  373 1100622 1621 1640 46147 46166 TAGAACCATTACTATTATCA  31  374 1100623 1623 1642 46149 46168 TCTAGAACCATTACTATTAT  81  375 1100624 1624 1643 46150 46169 TTCTAGAACCATTACTATTA  60  376 1100625 1625 1644 46151 46170 CTTCTAGAACCATTACTATT  78  377 1100626 1626 1645 46152 46171 CCTTCTAGAACCATTACTAT  46  378 1100627 1627 1646 46153 46172 TCCTTCTAGAACCATTACTA  60  379 1100628 1679 1698 46205 46224 ACACAAGAAAACACTGGAGC  36  380 1100629 1681 1700 46207 46226 CAACACAAGAAAACACTGGA  72  381 1100630 1691 1710 46217 46236 TCAGAGAAAACAACACAAGA  70  382 1100631 1721 1740 46247 46266 AATGAAAACCAGGTAGCAGA  64  383 1100632 1723 1742 46249 46268 ATAATGAAAACCAGGTAGCA  77  384 1100633 1727 1746 46253 46272 GAAAATAATGAAAACCAGGT  63  385 1100634 1731 1750 46257 46276 GTGGGAAAATAATGAAAACC  35  386 1100635 1732 1751 46258 46277 TGTGGGAAAATAATGAAAAC  73  387 1100636 1733 1752 46259 46278 TTGTGGGAAAATAATGAAAA  71  388 1100637 1743 1762 46269 46288 TTCAAAAGAATTGTGGGAAA  81  389 1100638 1745 1764 46271 46290 CTTTCAAAAGAATTGTGGGA  44  390 1100639 1746 1765 46272 46291 TCTTTCAAAAGAATTGTGGG  42  391 1100640 1748 1767 46274 46293 CATCTTTCAAAAGAATTGTG  66  392 1100641 1749 1768 46275 46294 CCATCTTTCAAAAGAATTGT  26  393 1100642 1750 1769 46276 46295 ACCATCTTTCAAAAGAATTG  52  394 1100643 1754 1773 46280 46299 GATTACCATCTTTCAAAAGA  44  395 1100644 1757 1776 46283 46302 AAAGATTACCATCTTTCAAA  96  396 1100646 1759 1778 46285 46304 GAAAAGATTACCATCTTTCA  39  397 1100648 1761 1780 46287 46306 CAGAAAAGATTACCATCTTT  91  398 1100649 1762 1781 46288 46307 TCAGAAAAGATTACCATCTT  66  399 1100650 1763 1782 46289 46308 CTCAGAAAAGATTACCATCT  67  400 1100651 1764 1783 46290 46309 CCTCAGAAAAGATTACCATC  62  401 1100652 1772 1791 46298 46317 ACGCTAAACCTCAGAAAAGA  67  402 1100653 1804 1823 46330 46349 CATGAAATAATGATCCCATC  98  403 1100654 1805 1824 46331 46350 TCATGAAATAATGATCCCAT  60  404 1100655 1806 1825 46332 46351 GTCATGAAATAATGATCCCA  44  405 1100656 1807 1826 46333 46352 AGTCATGAAATAATGATCCC  94  406 1100657 1808 1827 46334 46353 CAGTCATGAAATAATGATCC  68  407 1100658 1809 1828 46335 46354 CCAGTCATGAAATAATGATC  54  408 1100659 1810 1829 46336 46355 ACCAGTCATGAAATAATGAT  80  409 1100660 1819 1838 46345 46364 TAGGAACGCACCAGTCATGA  38  410 1100661 1821 1840 46347 46366 TTTAGGAACGCACCAGTCAT  50  411 1100662 1822 1841 46348 46367 GTTTAGGAACGCACCAGTCA  55  412 1100663 1823 1842 46349 46368 AGTTTAGGAACGCACCAGTC  35  413 1100664 1824 1843 46350 46369 GAGTTTAGGAACGCACCAGT  31  414 1100665 1825 1844 46351 46370 AGAGTTTAGGAACGCACCAG  22  415 1100666 1826 1845 46352 46371 CAGAGTTTAGGAACGCACCA  16  416 1100667 1827 1846 46353 46372 TCAGAGTTTAGGAACGCACC  13  417 1100668 1829 1848 46355 46374 TTTCAGAGTTTAGGAACGCA  16  418 1100669 1835 1854 46361 46380 GGCTGATTTCAGAGTTTAGG  12  419 1100670 1860 1879 46386 46405 CATTTATTCTCAAGTACTTG  25  420 1100671 1861 1880 46387 46406 TCATTTATTCTCAAGTACTT  40  421 1100672 1862 1881 46388 46407 CTCATTTATTCTCAAGTACT  31  422 1100673 1863 1882 46389 46408 GCTCATTTATTCTCAAGTAC  12  423 1100674 1868 1887 46394 46413 AAAATGCTCATTTATTCTCA  49  424 1100675 1889 1908 46415 46434 GCACATGCTCACACATTTTA  43  425 1100676 1927 1946 46453 46472 GATATAAGTGAAAAGACATT  80  426 1100677 1953 1972 46479 46498 GGGTTGCAACAAAGCTGTAA  40  427 1100678 1980 1999 46506 46525 AAGGAAAAAATAAGGCGCAG  71  428 1100679 1982 2001 46508 46527 GAAAGGAAAAAATAAGGCGC  97  429 1100680 2004 2023 46530 46549 CCTAGTTTTCTCAATTGGAG  98  430 1100682 2006 2025 46532 46551 CTCCTAGTTTTCTCAATTGG  53  431 1100684 2009 2028 46535 46554 CTTCTCCTAGTTTTCTCAAT  45  432 1100685 2014 2033 46540 46559 CTATGCTTCTCCTAGTTTTC  50  433 1100686 2015 2034 46541 46560 ACTATGCTTCTCCTAGTTTT  61  434 1100687 2023 2042 46549 46568 GCCTGCATACTATGCTTCTC  68  435 1100688 2024 2043 46550 46569 TGCCTGCATACTATGCTTCT  92  436 1100689 2030 2049 46556 46575 GAGACTTGCCTGCATACTAT  33  437 1100690 2045 2064 46571 46590 GTCTTCTAACAGAAGGAGAC 125  438 1100691 2046 2065 46572 46591 AGTCTTCTAACAGAAGGAGA 137  439 1100692 2047 2066 46573 46592 TAGTCTTCTAACAGAAGGAG  72  440 1100693 2048 2067 46574 46593 TTAGTCTTCTAACAGAAGGA  81  441 1100694 2049 2068 46575 46594 TTTAGTCTTCTAACAGAAGG  85  442 1100695 2050 2069 46576 46595 GTTTAGTCTTCTAACAGAAG  42  443 1100696 2052 2071 46578 46597 ATGTTTAGTCTTCTAACAGA  43  444 1100697 2054 2073 46580 46599 GTATGTTTAGTCTTCTAACA  19  445 1100698 2091 2110 46617 46636 GGCCAAATTTCATGTATCAT  35  446 1100699 2093 2112 46619 46638 AAGGCCAAATTTCATGTATC  48  447 1100700 2094 2113 46620 46639 GAAGGCCAAATTTCATGTAT  34  448 1100701 2097 2116 46623 46642 ATTGAAGGCCAAATTTCATG  48  449 1100702 2105 2124 46631 46650 CTATTAAAATTGAAGGCCAA  77  450 1100703 2106 2125 46632 46651 GCTATTAAAATTGAAGGCCA  48  451 1100704 2108 2127 46634 46653 CTGCTATTAAAATTGAAGGC  25  452 1100705 2109 2128 46635 46654 ACTGCTATTAAAATTGAAGG  35  453 1100706 2110 2129 46636 46655 AACTGCTATTAAAATTGAAG  71  454 1100707 2111 2130 46637 46656 AAACTGCTATTAAAATTGAA  78  455 1100708 2112 2131 46638 46657 AAAACTGCTATTAAAATTGA 111  456 1100709 2168 2187 46694 46713 CATGACTCAACTGTAAAGAG  29  457 1100710 2204 2223 46730 46749 TACCTACTAAAAGATGTGAA  85  458 1100711 2205 2224 46731 46750 ATACCTACTAAAAGATGTGA  74  459 1100712 2206 2225 46732 46751 TATACCTACTAAAAGATGTG  77  460 1100713 2207 2226 46733 46752 CTATACCTACTAAAAGATGT 103  461 1100714 2208 2227 46734 46753 GCTATACCTACTAAAAGATG  55  462 1100715 2209 2228 46735 46754 AGCTATACCTACTAAAAGAT  63  463 1100716 2210 2229 46736 46755 AAGCTATACCTACTAAAAGA  73  464 1100718 2212 2231 46738 46757 ACAAGCTATACCTACTAAAA  60  465 1100720 2214 2233 46740 46759 TGACAAGCTATACCTACTAA  45  466 1100721 2216 2235 46742 46761 TTTGACAAGCTATACCTACT  57  467 1100722 2225 2244 46751 46770 ATCACCATCTTTGACAAGCT  30  468 1100723 2229 2248 46755 46774 CCAGATCACCATCTTTGACA  22  469 1100724 2231 2250 46757 46776 TTCCAGATCACCATCTTTGA  38  470 1100725 2232 2251 46758 46777 GTTCCAGATCACCATCTTTG   8  471 1100726 2233 2252 46759 46778 TGTTCCAGATCACCATCTTT  39  472 1100727 2234 2253 46760 46779 ATGTTCCAGATCACCATCTT  38  473 1100728 2236 2255 46762 46781 TCATGTTCCAGATCACCATC  83  474 1100729 2237 2256 46763 46782 TTCATGTTCCAGATCACCAT  16  475 1100730 2238 2257 46764 46783 TTTCATGTTCCAGATCACCA  15  476 1100731 2239 2258 46765 46784 TTTTCATGTTCCAGATCACC  22  477 1100732 2244 2263 46770 46789 AATTATTTTCATGTTCCAGA  12  478 1100733 2251 2270 46777 46796 ATTAGTAAATTATTTTCATG  76  479 1100734 2261 2280 46787 46806 ACATATTTTCATTAGTAAAT 131  480 1100735 2262 2281 46788 46807 AACATATTTTCATTAGTAAA  82  481 1100736 2273 2292 46799 46818 GTATAAATTTAAACATATTT  82  482 1100737 2276 2295 46802 46821 ACAGTATAAATTTAAACATA 101  483 1100738 2277 2296 46803 46822 CACAGTATAAATTTAAACAT  86  484 1100739 2278 2297 46804 46823 TCACAGTATAAATTTAAACA  96  485 1100740 2279 2298 46805 46824 ATCACAGTATAAATTTAAAC 116  486 1100741 2280 2299 46806 46825 AATCACAGTATAAATTTAAA  79  487 1100742 2282 2301 46808 46827 CAAATCACAGTATAAATTTA  92  488 1100743 2288 2307 46814 46833 AAGTGTCAAATCACAGTATA  58  489 1100744 2291 2310 46817 46836 TGCAAGTGTCAAATCACAGT  28  490 1100745 2305 2324 46831 46850 CTATCTAAACATGATGCAAG  63  491 1100746 2306 2325 46832 46851 GCTATCTAAACATGATGCAA  62  492 1100747 2307 2326 46833 46852 AGCTATCTAAACATGATGCA  87  493 1100748 2309 2328 46835 46854 TAAGCTATCTAAACATGATG  77  494 1100749 2310 2329 46836 46855 TTAAGCTATCTAAACATGAT  89  495 1100750 2311 2330 46837 46856 CTTAAGCTATCTAAACATGA  81  496 1100751 2312 2331 46838 46857 TCTTAAGCTATCTAAACATG  52  497 1100752 2314 2333 46840 46859 GTTCTTAAGCTATCTAAACA  63  498 1100754 2346 2365 46872 46891 TTATAGATCCACTAAGTACT  71  499 1100756 2355 2374 46881 46900 CTTTCTTATTTATAGATCCA  22  500 1100757 2357 2376 46883 46902 GACTTTCTTATTTATAGATC  32  501 1100758 2371 2390 46897 46916 TTATCAAAACTATGGACTTT  89  502 1100759 2372 2391 46898 46917 TTTATCAAAACTATGGACTT  61  503 1100760 2373 2392 46899 46918 ATTTATCAAAACTATGGACT  56  504 1100761 2375 2394 46901 46920 ATATTTATCAAAACTATGGA  87  505 1100762 2376 2395 46902 46921 AATATTTATCAAAACTATGG  75  506 1100763 2384 2403 46910 46929 TTAAAGAGAATATTTATCAA 123  507 1100764 2386 2405 46912 46931 AATTAAAGAGAATATTTATC 107  508 1100765 2392 2411 46918 46937 CATCTCAATTAAAGAGAATA 172  509 1100766 2395 2414 46921 46940 GTACATCTCAATTAAAGAGA  36  510 1100767 2422 2441 46948 46967 TCCTATTGACCCAGCAAGAA  38  511 1100768 2426 2445 46952 46971 ACTATCCTATTGACCCAGCA  24  512 1100769 2430 2449 46956 46975 TGATACTATCCTATTGACCC  25  513 1100770 2444 2463 46970 46989 GGTTTTCACCAAAATGATAC  50  514 1100771 2463 2482 46989 47008 ACATCAATTTCAGAGACATG  33  515 1100772 2464 2483 46990 47009 AACATCAATTTCAGAGACAT  24  516 1100773 2465 2484 46991 47010 AAACATCAATTTCAGAGACA  48  517 1100774 2472 2491 46998 47017 GAAACTAAAACATCAATTTC 104  518 1100775 2475 2494 47001 47020 ACTGAAACTAAAACATCAAT 114  519 1100776 2516 2535 47042 47061 AAAGAGCTTCAAAAGGAGAT  55  520 1100777 2525 2544 47051 47070 CAACATTCAAAAGAGCTTCA  40  521 1100778 2526 2545 47052 47071 TCAACATTCAAAAGAGCTTC  53  522 1100779 2527 2546 47053 47072 TTCAACATTCAAAAGAGCTT  65  523 1100780 2530 2549 47056 47075 CAATTCAACATTCAAAAGAG  64  524 1100781 2531 2550 47057 47076 ACAATTCAACATTCAAAAGA  97  525 1100782 2532 2551 47058 47077 AACAATTCAACATTCAAAAG  68  526 1100783 2533 2552 47059 47078 GAACAATTCAACATTCAAAA  39  527 1100784 2534 2553 47060 47079 TGAACAATTCAACATTCAAA  53  528 1100785 2535 2554 47061 47080 ATGAACAATTCAACATTCAA  57  529 1100786 2536 2555 47062 47081 TATGAACAATTCAACATTCA  67  530 1100787 2537 2556 47063 47082 TTATGAACAATTCAACATTC  50  531 1100788 2539 2558 47065 47084 GCTTATGAACAATTCAACAT  21  532 1100790 2543 2562 47069 47088 TTTAGCTTATGAACAATTCA  60  533 1100792 2553 2572 47079 47098 TTTCTTGGATTTTAGCTTAT  32  534 1100793 2561 2580 47087 47106 AGCTGAAATTTCTTGGATTT  48  535 1100794 2562 2581 47088 47107 CAGCTGAAATTTCTTGGATT  54  536 1100795 2563 2582 47089 47108 TCAGCTGAAATTTCTTGGAT  38  537 1100796 2564 2583 47090 47109 GTCAGCTGAAATTTCTTGGA  17  538 1100797 2566 2585 47092 47111 TTGTCAGCTGAAATTTCTTG  30  539 1100798 2568 2587 47094 47113 AGTTGTCAGCTGAAATTTCT  33  540 1100799 2569 2588 47095 47114 AAGTTGTCAGCTGAAATTTC  34  541 1100800 2570 2589 47096 47115 GAAGTTGTCAGCTGAAATTT  84  542 1100801 2571 2590 47097 47116 CGAAGTTGTCAGCTGAAATT  23  543 1100802 2572 2591 47098 47117 TCGAAGTTGTCAGCTGAAAT  16  544 1100803 2573 2592 47099 47118 TTCGAAGTTGTCAGCTGAAA  24  545 1100804 2574 2593 47100 47119 TTTCGAAGTTGTCAGCTGAA  26  546 1100805 2576 2595 47102 47121 ATTTTCGAAGTTGTCAGCTG  42  547 1100806 2583 2602 47109 47128 TATTATAATTTTCGAAGTTG  53  548 1100807 2585 2604 47111 47130 CATATTATAATTTTCGAAGT  71  549 1100808 2590 2609 47116 47135 TATACCATATTATAATTTTC  56  550 1100809 2595 2614 47121 47140 GGCAATATACCATATTATAA  14  551 1100810 2597 2616 47123 47142 AGGGCAATATACCATATTAT  17  552 1100811 2598 2617 47124 47143 GAGGGCAATATACCATATTA  25  553 1100812 2642 2661 47168 47187 ATCAAAAAACTTTCCCTGAT  79  554 1100813 2643 2662 47169 47188 GATCAAAAAACTTTCCCTGA  70  555 1100814 2644 2663 47170 47189 AGATCAAAAAACTTTCCCTG  58  556 1100815 2646 2665 47172 47191 CTAGATCAAAAAACTTTCCC  75  557 1100816 2647 2666 47173 47192 CCTAGATCAAAAAACTTTCC  58  558 1100817 2648 2667 47174 47193 TCCTAGATCAAAAAACTTTC  91  559 1100818 2649 2668 47175 47194 ATCCTAGATCAAAAAACTTT  62  560 1100819 2650 2669 47176 47195 AATCCTAGATCAAAAAACTT  62  561 1100820 2651 2670 47177 47196 AAATCCTAGATCAAAAAACT  92  562 1100821 2652 2671 47178 47197 TAAATCCTAGATCAAAAAAC  75  563 1100822 2656 2675 47182 47201 GCAATAAATCCTAGATCAAA  50  564 1100823 2657 2676 47183 47202 AGCAATAAATCCTAGATCAA  51  565 1100824 2658 2677 47184 47203 TAGCAATAAATCCTAGATCA  66  566 1100826 2660 2679 47186 47205 GTTAGCAATAAATCCTAGAT  29  567 1100828 2700 2719 47226 47245 AATCATAAATAAAAGATATT  87  568 1100829 2701 2720 47227 47246 TAATCATAAATAAAAGATAT  98  569 1100830 2712 2731 47238 47257 AAGCTATTTTATAATCATAA  72  570 1100831 2714 2733 47240 47259 AAAAGCTATTTTATAATCAT  78  571 1100832 2739 2758 47265 47284 CTTAAAAAATCTGTTATATC  78  572 1100833 2741 2760 47267 47286 GACTTAAAAAATCTGTTATA  83  573 1100834 2742 2761 47268 47287 TGACTTAAAAAATCTGTTAT  88  574 1100835 2743 2762 47269 47288 ATGACTTAAAAAATCTGTTA  67  575 1100836 2744 2763 47270 47289 AATGACTTAAAAAATCTGTT  77  576 1100837 2745 2764 47271 47290 TAATGACTTAAAAAATCTGT  83  577 1100838 2753 2772 47279 47298 GCACAAAATAATGACTTAAA  38  578 1100839 2754 2773 47280 47299 GGCACAAAATAATGACTTAA   8  579 1100840 2755 2774 47281 47300 TGGCACAAAATAATGACTTA  28  580 1100841 2756 2775 47282 47301 TTGGCACAAAATAATGACTT  42  581 1100842 2758 2777 47284 47303 GATTGGCACAAAATAATGAC  39  582 1100843 2778 2797 47304 47323 AAGGGAAACTTCAGAAAACT  41  583 1100844 2779 2798 47305 47324 TAAGGGAAACTTCAGAAAAC  74  584 1100845 2780 2799 47306 47325 GTAAGGGAAACTTCAGAAAA  42  585 1100846 2781 2800 47307 47326 TGTAAGGGAAACTTCAGAAA  24  586 1100847 2810 2829 47336 47355 TTAGATTTTAAAATAAAGCT  95  587 1100848 2830 2849 47356 47375 TTTAACTATTAAAAGAAACT  91  588 1100849 2840 2859 47366 47385 CTGAAACATTTTTAACTATT  60  589 1100850 2849 2868 47375 47394 ATAATTCTTCTGAAACATTT  59  590 1100851 2851 2870 47377 47396 TTATAATTCTTCTGAAACAT  58  591 1100852 2852 2871 47378 47397 TTTATAATTCTTCTGAAACA  79  592 1100853 2853 2872 47379 47398 TTTTATAATTCTTCTGAAAC 112  593 1100854 2854 2873 47380 47399 GTTTTATAATTCTTCTGAAA  58  594 1100855 2855 2874 47381 47400 AGTTTTATAATTCTTCTGAA  61  595 1100856 2856 2875 47382 47401 AAGTTTTATAATTCTTCTGA  59  596 1100857 2858 2877 47384 47403 TAAAGTTTTATAATTCTTCT  87  597 1100858 2859 2878 47385 47404 TTAAAGTTTTATAATTCTTC  79  598 1100859 2862 2881 47388 47407 GTTTTAAAGTTTTATAATTC  96  599 1100860 2867 2886 47393 47412 TTGCAGTTTTAAAGTTTTAT  82  600 1100862 2908 2927 47434 47453 TTTTTAAATCTTGAGGGAGT  51  601 1100864 2912 2931 47438 47457 TAGCTTTTTAAATCTTGAGG  11  602 1100865 2913 2932 47439 47458 TTAGCTTTTTAAATCTTGAG  11  603 1100866 2914 2933 47440 47459 TTTAGCTTTTTAAATCTTGA  60  604 1100867 2915 2934 47441 47460 ATTTAGCTTTTTAAATCTTG  84  605 1100868 2916 2935 47442 47461 TATTTAGCTTTTTAAATCTT  96  606 1100869 2924 2943 47450 47469 TCTTAAAATATTTAGCTTTT  87  607 1100870 2925 2944 47451 47470 GTCTTAAAATATTTAGCTTT  45  608 1100871 2926 2945 47452 47471 AGTCTTAAAATATTTAGCTT  58  609 1100872 2927 2946 47453 47472 CAGTCTTAAAATATTTAGCT  85  610 1100873 2928 2947 47454 47473 TCAGTCTTAAAATATTTAGC   7  611 1100874 2929 2948 47455 47474 TTCAGTCTTAAAATATTTAG  78  612 1100875 2930 2949 47456 47475 GTTCAGTCTTAAAATATTTA  26  613 1100876 2932 2951 47458 47477 ATGTTCAGTCTTAAAATATT  47  614 1100877 2935 2954 47461 47480 TAAATGTTCAGTCTTAAAAT  98  615 1100878 2936 2955 47462 47481 ATAAATGTTCAGTCTTAAAA  94  616 1100879 2948 2967 47474 47493 GTAATAATTAACATAAATGT  95  617 1100880 2951 2970 47477 47496 CTGGTAATAATTAACATAAA 110  618 1100881 2952 2971 47478 47497 ACTGGTAATAATTAACATAA  54  619 1100882 2974 2993 47500 47519 CCATGGAAAATATGACAAAC  44  620 1100883 2982 3001 47508 47527 ACAAATATCCATGGAAAATA  76  621 1100884 2983 3002 47509 47528 AACAAATATCCATGGAAAAT  70  622 1100885 2984 3003 47510 47529 GAACAAATATCCATGGAAAA  43  623 1100886 2985 3004 47511 47530 TGAACAAATATCCATGGAAA  49  624 1100887 2987 3006 47513 47532 AATGAACAAATATCCATGGA  50  625 1100888 2988 3007 47514 47533 TAATGAACAAATATCCATGG  43  626 1100889 2989 3008 47515 47534 GTAATGAACAAATATCCATG  27  627 1100890 2990 3009 47516 47535 GGTAATGAACAAATATCCAT  52  628 1100891 2991 3010 47517 47536 AGGTAATGAACAAATATCCA  40  629 1100892 2996 3015 47522 47541 GAAAAAGGTAATGAACAAAT  84  630 1100893 3031 3050 47557 47576 CAAGTGTATGAAAAGTTTAA  75  631 1100894 3038 3057 47564 47583 ATCAATTCAAGTGTATGAAA  83  632 1100895 3040 3059 47566 47585 TCATCAATTCAAGTGTATGA  35  633 1100896 3041 3060 47567 47586 CTCATCAATTCAAGTGTATG  42  634 1100898 3043 3062 47569 47588 AGCTCATCAATTCAAGTGTA  18  635 1100900 3045 3064 47571 47590 GTAGCTCATCAATTCAAGTG  16  636 1100901 3046 3065 47572 47591 GGTAGCTCATCAATTCAAGT  17  637 1100902 3047 3066 47573 47592 AGGTAGCTCATCAATTCAAG  20  638 1100903 3048 3067 47574 47593 TAGGTAGCTCATCAATTCAA  16  639 1100904 3049 3068 47575 47594 TTAGGTAGCTCATCAATTCA  33  640 1100905 3051 3070 47577 47596 TATTAGGTAGCTCATCAATT  36  641 1100906 3060 3079 47586 47605 TCATTTTTATATTAGGTAGC  15  642 1100907 3061 3080 47587 47606 CTCATTTTTATATTAGGTAG  11  643 1100908 3062 3081 47588 47607 TCTCATTTTTATATTAGGTA 112  644 1100909 3069 3088 47595 47614 TTGGTTTTCTCATTTTTATA  23  645 1100910 3070 3089 47596 47615 ATTGGTTTTCTCATTTTTAT  21  646 1100911 3071 3090 47597 47616 TATTGGTTTTCTCATTTTTA  15  647 1100912 3072 3091 47598 47617 ATATTGGTTTTCTCATTTTT  34  648 1100913 3073 3092 47599 47618 CATATTGGTTTTCTCATTTT  24  649 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   8   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   6   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   6   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT  78   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   6   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   6   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   4   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   9   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   4   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   6   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   8   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   8   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   6   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   6   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   7   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   5   45 1100915 3075 3094 47601 47620 TGCATATTGGTTTTCTCATT   8  650 1100916 3076 3095 47602 47621 ATGCATATTGGTTTTCTCAT  10  651 1100917 3077 3096 47603 47622 AATGCATATTGGTTTTCTCA   8  652 1100918 3079 3098 47605 47624 AAAATGCATATTGGTTTTCT  22  653 1100919 3116 3135 47642 47661 TATATATGAACTTTATAAAC  74  654 1100920 3119 3138 47645 47664 GGGTATATATGAACTTTATA   8  655 1100921 3122 3141 47648 47667 CTAGGGTATATATGAACTTT  21  656 1100922 3123 3142 47649 47668 ACTAGGGTATATATGAACTT  24  657 1100923 3124 3143 47650 47669 AACTAGGGTATATATGAACT  24  658 1100924 3133 3152 47659 47678 AAGTGCTTTAACTAGGGTAT  16  659 1100925 3134 3153 47660 47679 TAAGTGCTTTAACTAGGGTA  19  660 1100926 3135 3154 47661 47680 TTAAGTGCTTTAACTAGGGT  55  661 1100927 3140 3159 47666 47685 TTTTCTTAAGTGCTTTAACT  53  662 1100928 3146 3165 47672 47691 GCCATATTTTCTTAAGTGCT  18  663 1100929 3162 3181 47688 47707 ACTAAAAGTCAAACATGCCA  43  664 1100930 3164 3183 47690 47709 GAACTAAAAGTCAAACATGC  44  665 1100931 3507 3526 48033 48052 GCTCTGCTTTAAAAACTCTC  89  666 1100932 3536 3555 48062 48081 CACATTCAAACGCATCCAGT  49  667 1100933 3537 3556 48063 48082 ACACATTCAAACGCATCCAG  39  668 1100935 3540 3559 48066 48085 CAAACACATTCAAACGCATC  85  669 1100937 3542 3561 48068 48087 CACAAACACATTCAAACGCA  69  670 1100938 3544 3563 48070 48089 TACACAAACACATTCAAACG  76  671 1100939 3545 3564 48071 48090 CTACACAAACACATTCAAAC  57  672 1100940 3546 3565 48072 48091 ACTACACAAACACATTCAAA  82  673 1100941 3549 3568 48075 48094 CAAACTACACAAACACATTC  76  674 1100942 3550 3569 48076 48095 ACAAACTACACAAACACATT  95  675 1100943 3551 3570 48077 48096 AACAAACTACACAAACACAT  66  676 1100944 3554 3573 48080 48099 CACAACAAACTACACAAACA  65  677 1100945 3555 3574 48081 48100 TCACAACAAACTACACAAAC  92  678 1100946 3556 3575 48082 48101 TTCACAACAAACTACACAAA  88  679 1100947 3558 3577 48084 48103 ATTTCACAACAAACTACACA  78  680 1100948 3559 3578 48085 48104 AATTTCACAACAAACTACAC  66  681 1100949 3560 3579 48086 48105 CAATTTCACAACAAACTACA  93  682 1100950 3563 3582 48089 48108 TAACAATTTCACAACAAACT  89  683 1100951 3564 3583 48090 48109 GTAACAATTTCACAACAAAC  38  684 1100952 3565 3584 48091 48110 TGTAACAATTTCACAACAAA  52  685 1100953 3566 3585 48092 48111 ATGTAACAATTTCACAACAA  35  686 1100954 3567 3586 48093 48112 AATGTAACAATTTCACAACA  61  687 1100955 3568 3587 48094 48113 AAATGTAACAATTTCACAAC  73  688 1100956 3569 3588 48095 48114 TAAATGTAACAATTTCACAA 104  689 1100957 3570 3589 48096 48115 CTAAATGTAACAATTTCACA  87  690 1100958 3571 3590 48097 48116 GCTAAATGTAACAATTTCAC  46  691 1100959 3576 3595 48102 48121 TGCCTGCTAAATGTAACAAT  66  692 1100960 3582 3601 48108 48127 TGGATCTGCCTGCTAAATGT  42  693 1100961 3616 3635 48142 48161 CAACCCCACCAAGATGACAG  68  694 1100962 3621 3640 48147 48166 TAAGCCAACCCCACCAAGAT  88  695 1100963 3622 3641 48148 48167 TTAAGCCAACCCCACCAAGA  53  696 1100964 3626 3645 48152 48171 AAATTTAAGCCAACCCCACC  83  697 1100965 3627 3646 48153 48172 TAAATTTAAGCCAACCCCAC 134  698 1100966 3633 3652 48159 48178 GTCAATTAAATTTAAGCCAA  41  699 1100967 3636 3655 48162 48181 ACAGTCAATTAAATTTAAGC  72  700 1100968 3644 3663 48170 48189 GAATCTAAACAGTCAATTAA  75  701 1100969 3648 3667 48174 48193 AATGGAATCTAAACAGTCAA  78  702 1100971 3668 3687 48194 48213 TACTGGCCAATCAATTAAGA  73  703 1100973 3672 3691 48198 48217 TTCATACTGGCCAATCAATT  60  704 1100974 3674 3693 48200 48219 TTTTCATACTGGCCAATCAA  64  705 1100975 3676 3695 48202 48221 TCTTTTCATACTGGCCAATC  71  706 1100976 3677 3696 48203 48222 ATCTTTTCATACTGGCCAAT  52  707 1100977 3678 3697 48204 48223 CATCTTTTCATACTGGCCAA  50  708 1100978 3679 3698 48205 48224 GCATCTTTTCATACTGGCCA  35  709 1100979 3680 3699 48206 48225 GGCATCTTTTCATACTGGCC  29  710 1100980 3681 3700 48207 48226 TGGCATCTTTTCATACTGGC  14  711 1100981 3682 3701 48208 48227 CTGGCATCTTTTCATACTGG 104  712 1100982 3684 3703 48210 48229 CACTGGCATCTTTTCATACT  28  713 1100983 3699 3718 48225 48244 TACTATGGTTACTTGCACTG  35  714 1100984 3730 3749 48256 48275 TATAGCTTTGAATAATTTTT 121  715 1100985 3740 3759 48266 48285 ATGTATAAACTATAGCTTTG  37  716 1100986 3742 3761 48268 48287 TGATGTATAAACTATAGCTT  53  717 1100987 3747 3766 48273 48292 GTACCTGATGTATAAACTAT  51  718 1100988 3749 3768 48275 48294 CAGTACCTGATGTATAAACT  21  719 1100989 3750 3769 48276 48295 GCAGTACCTGATGTATAAAC  11  720 1100990 3751 3770 48277 48296 GGCAGTACCTGATGTATAAA  10  721 1100991 3752 3771 48278 48297 TGGCAGTACCTGATGTATAA  10  722 1100992 3753 3772 48279 48298 ATGGCAGTACCTGATGTATA  16  723 1100993 3754 3773 48280 48299 AATGGCAGTACCTGATGTAT  48  724 1100994 3755 3774 48281 48300 AAATGGCAGTACCTGATGTA  40  725 1100995 3757 3776 48283 48302 GTAAATGGCAGTACCTGATG  15  726 1100996 3764 3783 48290 48309 GTTTACAGTAAATGGCAGTA  18  727 1100997 3766 3785 48292 48311 TGGTTTACAGTAAATGGCAG  16  728 1100998 3768 3787 48294 48313 GGTGGTTTACAGTAAATGGC  25  729 1100999 3769 3788 48295 48314 AGGTGGTTTACAGTAAATGG  17  730 1101000 3771 3790 48297 48316 GCAGGTGGTTTACAGTAAAT  13  731 1101001 3782 3801 48308 48327 CTGACTTTCTTGCAGGTGGT  21  732 1101002 3785 3804 48311 48330 TTCCTGACTTTCTTGCAGGT 102  733 1101003 3786 3805 48312 48331 GTTCCTGACTTTCTTGCAGG  45  734 1101004 3788 3807 48314 48333 TTGTTCCTGACTTTCTTGCA  27  735 1101005 3791 3810 48317 48336 TAGTTGTTCCTGACTTTCTT  50  736 1101007 3793 3812 48319 48338 TTTAGTTGTTCCTGACTTTC  74  737 1101009 3838 3857 48364 48383 AATGGAAATCTTTAATACAC  64  738 1101010 3854 3873 48380 48399 CCAATTAGTAAAACAAAATG 104  739 1101011 3861 3880 48387 48406 GATGTTCCCAATTAGTAAAA  29  740 1101012 3863 3882 48389 48408 AAGATGTTCCCAATTAGTAA  29  741 1101013 3864 3883 48390 48409 TAAGATGTTCCCAATTAGTA  47  742 1101014 3870 3889 48396 48415 AAACATTAAGATGTTCCCAA  35  743 1101015 3871 3890 48397 48416 TAAACATTAAGATGTTCCCA  45  744 1101016 3873 3892 48399 48418 ATTAAACATTAAGATGTTCC  55  745 1101017 3874 3893 48400 48419 TATTAAACATTAAGATGTTC  90  746 1101018 3875 3894 48401 48420 ATATTAAACATTAAGATGTT 113  747 1101019 3877 3896 48403 48422 AAATATTAAACATTAAGATG  86  748 1101020 3878 3897 48404 48423 TAAATATTAAACATTAAGAT  90  749 1101021 3884 3903 48410 48429 ATAGTTTAAATATTAAACAT  99  750 1101022 3886 3905 48412 48431 CAATAGTTTAAATATTAAAC 119  751 1101023 3887 3906 48413 48432 CCAATAGTTTAAATATTAAA 111  752 1101024 3888 3907 48414 48433 ACCAATAGTTTAAATATTAA  98  753 1101025 3890 3909 48416 48435 ATACCAATAGTTTAAATATT 110  754 1101026 3896 3915 48422 48441 AAAATGATACCAATAGTTTA  78  755 1101027 3897 3916 48423 48442 AAAAATGATACCAATAGTTT  96  756 1101028 3898 3917 48424 48443 GAAAAATGATACCAATAGTT  67  757 1101029 3899 3918 48425 48444 AGAAAAATGATACCAATAGT  61  758 1101030 3900 3919 48426 48445 TAGAAAAATGATACCAATAG  61  759 1101031 3902 3921 48428 48447 ATTAGAAAAATGATACCAAT  75  760 1101032 3903 3922 48429 48448 CATTAGAAAAATGATACCAA  74  761 1101033 3905 3924 48431 48450 TACATTAGAAAAATGATACC  74  762 1101034 3906 3925 48432 48451 ATACATTAGAAAAATGATAC 119  763 1101035 3907 3926 48433 48452 TATACATTAGAAAAATGATA  94  764 1101036 3912 3931 48438 48457 CAAATTATACATTAGAAAAA 138  765 1101037 3913 3932 48439 48458 ACAAATTATACATTAGAAAA  83  766 1101038 3914 3933 48440 48459 TACAAATTATACATTAGAAA  70  767 1101039 3915 3934 48441 48460 ATACAAATTATACATTAGAA 113  768 1101040 3916 3935 48442 48461 AATACAAATTATACATTAGA 105  769 1101041 3917 3936 48443 48462 TAATACAAATTATACATTAG  85  770 1101043 3919 3938 48445 48464 AGTAATACAAATTATACATT  98  771 1101045 3922 3941 48448 48467 CCCAGTAATACAAATTATAC  74  772 1101046 3923 3942 48449 48468 TCCCAGTAATACAAATTATA  50  773 1101047 3924 3943 48450 48469 ATCCCAGTAATACAAATTAT  40  774 1101048 3925 3944 48451 48470 GATCCCAGTAATACAAATTA  47  775 1101049 3929 3948 48455 48474 ACTTGATCCCAGTAATACAA  21  776 1101050 3930 3949 48456 48475 TACTTGATCCCAGTAATACA  30  777 1101051 3931 3950 48457 48476 ATACTTGATCCCAGTAATAC  32  778 1101052 3932 3951 48458 48477 CATACTTGATCCCAGTAATA  29  779 1101053 3935 3954 48461 48480 GTACATACTTGATCCCAGTA  89  780 1101054 3937 3956 48463 48482 CTGTACATACTTGATCCCAG  15  781 1101055 3941 3960 48467 48486 ACCACTGTACATACTTGATC  32  782 1101056 3942 3961 48468 48487 CACCACTGTACATACTTGAT  45  783 1101057 3947 3966 48473 48492 AGCATCACCACTGTACATAC  15  784 1101058 3948 3967 48474 48493 TAGCATCACCACTGTACATA  23  785 1101059 3950 3969 48476 48495 ACTAGCATCACCACTGTACA  79  786 1101060 3951 3970 48477 48496 TACTAGCATCACCACTGTAC  74  787 1101061 3960 3979 48486 48505 TTAAACTTCTACTAGCATCA  56  788 1101062 3964 3983 48490 48509 AGGCTTAAACTTCTACTAGC  33  789 1101063 3968 3987 48494 48513 TCCAAGGCTTAAACTTCTAC  27  790 1101064 3977 3996 48503 48522 AGTGGTATTTCCAAGGCTTA  23  791 1101065 3978 3997 48504 48523 AAGTGGTATTTCCAAGGCTT  13  792 1101066 3979 3998 48505 48524 AAAGTGGTATTTCCAAGGCT  18  793 1101067 3989 4008 48515 48534 TGAAAATATGAAAGTGGTAT  30  794 1101068 3990 4009 48516 48535 CTGAAAATATGAAAGTGGTA  47  795 1101069 3993 4012 48519 48538 CATCTGAAAATATGAAAGTG 105  796 1101070 3994 4013 48520 48539 ACATCTGAAAATATGAAAGT 111  797 1101071 3995 4014 48521 48540 GACATCTGAAAATATGAAAG  25  798 1101072 3996 4015 48522 48541 TGACATCTGAAAATATGAAA  84  799 1101073 3997 4016 48523 48542 ATGACATCTGAAAATATGAA  48  800 1101074 4004 4023 48530 48549 TAAATCCATGACATCTGAAA  59  801 1101075 4007 4026 48533 48552 CATTAAATCCATGACATCTG  36  802 1101076 4008 4027 48534 48553 TCATTAAATCCATGACATCT  51  803 1101077 4009 4028 48535 48554 CTCATTAAATCCATGACATC  96  804 1101079 4011 4030 48537 48556 TACTCATTAAATCCATGACA  53  805 1101081 4013 4032 48539 48558 ATTACTCATTAAATCCATGA  60  806 1101082 4015 4034 48541 48560 AAATTACTCATTAAATCCAT  62  807 1101083 4016 4035 48542 48561 TAAATTACTCATTAAATCCA 102  808 1101084 4017 4036 48543 48562 ATAAATTACTCATTAAATCC  71  809 1101085 4018 4037 48544 48563 CATAAATTACTCATTAAATC  75  810 1101086 4019 4038 48545 48564 ACATAAATTACTCATTAAAT 126  811 1101087 4020 4039 48546 48565 AACATAAATTACTCATTAAA  81  812 1101088 4021 4040 48547 48566 AAACATAAATTACTCATTAA  78  813 1101089 4022 4041 48548 48567 AAAACATAAATTACTCATTA 103  814 1101090 4023 4042 48549 48568 AAAAACATAAATTACTCATT  98  815 1101091 4044 4063 48570 48589 AGATTAACTATTCTGAATTT  89  816 1101092 4045 4064 48571 48590 GAGATTAACTATTCTGAATT  46  817 1101093 4046 4065 48572 48591 AGAGATTAACTATTCTGAAT  47  818 1101094 4047 4066 48573 48592 CAGAGATTAACTATTCTGAA  57  819 1101095 4048 4067 48574 48593 TCAGAGATTAACTATTCTGA  74  820 1101096 4051 4070 48577 48596 AGATCAGAGATTAACTATTC  34  821 1101097 4052 4071 48578 48597 TAGATCAGAGATTAACTATT  42  822 1101098 4057 4076 48583 48602 GGTTTTAGATCAGAGATTAA  22  823 1101099 4058 4077 48584 48603 TGGTTTTAGATCAGAGATTA  17  824 1101100 4059 4078 48585 48604 ATGGTTTTAGATCAGAGATT  23  825 1101101 4061 4080 48587 48606 TGATGGTTTTAGATCAGAGA   8  826 1101102 4079 4098 48605 48624 ACCGTAAAAAACATAGATTG  47  827 1101103 4081 4100 48607 48626 TTACCGTAAAAAACATAGAT  62  828 1101104 4099 4118 48625 48644 ACTGAAATATTTACATGATT  67  829 1101105 4108 4127 48634 48653 GTTTATATTACTGAAATATT  86  830 1101106 4111 4130 48637 48656 ACAGTTTATATTACTGAAAT 116  831 1101107 4112 4131 48638 48657 AACAGTTTATATTACTGAAA  91  832 1101108 4113 4132 48639 48658 AAACAGTTTATATTACTGAA  86  833 1101109 4114 4133 48640 48659 CAAACAGTTTATATTACTGA 116  834 1101110 4115 4134 48641 48660 TCAAACAGTTTATATTACTG  70  835 1101111 4117 4136 48643 48662 TTTCAAACAGTTTATATTAC  86  836 1101112 4120 4139 48646 48665 CCTTTTCAAACAGTTTATAT  63  837 1101113 4121 4140 48647 48666 GCCTTTTCAAACAGTTTATA  36  838 1101115 4124 4143 48650 48669 GCAGCCTTTTCAAACAGTTT  31  839 1101117 4126 4145 48652 48671 CAGCAGCCTTTTCAAACAGT  27  840 1101118 4128 4147 48654 48673 TGCAGCAGCCTTTTCAAACA  36  841 1101119 4138 4157 48664 48683 AGAGTTTACCTGCAGCAGCC  36  842 1101120 4140 4159 48666 48685 ATAGAGTTTACCTGCAGCAG  21  843 1101121 4141 4160 48667 48686 TATAGAGTTTACCTGCAGCA  14  844 1101122 4142 4161 48668 48687 GTATAGAGTTTACCTGCAGC  15  845 1101123 4144 4163 48670 48689 TAGTATAGAGTTTACCTGCA  32  846 1101124 4169 4188 48695 48714 ATTGTAAATTATTTGGCCAA  78  847 1101125 4170 4189 48696 48715 AATTGTAAATTATTTGGCCA  84  848 1101126 4171 4190 48697 48716 GAATTGTAAATTATTTGGCC  57  849 1101127 4172 4191 48698 48717 TGAATTGTAAATTATTTGGC  44  850 1101128 4173 4192 48699 48718 GTGAATTGTAAATTATTTGG  26  851 1101129 4178 4197 48704 48723 ATTCTGTGAATTGTAAATTA  42  852 1101130 4191 4210 48717 48736 CCTTAAATAAAATATTCTGT  87  853 1101131 4197 4216 48723 48742 GCACCACCTTAAATAAAATA  62  854 1101132 4200 4219 48726 48745 AAAGCACCACCTTAAATAAA  83  855 1101133 4224 4243 48750 48769 ATCAAGTTTTAAGGACAAAA  56  856 1101134 4226 4245 48752 48771 AAATCAAGTTTTAAGGACAA  88  857 1101135 4227 4246 48753 48772 AAAATCAAGTTTTAAGGACA  84  858 1101136 4228 4247 48754 48773 AAAAATCAAGTTTTAAGGAC  94  859 1101137 4236 4255 48762 48781 AAGTTAAGAAAAATCAAGTT  82  860 1101138 4253 4272 48779 48798 CTTTGGCATCATGAATAAAG  35  861 1101139 4330 4349 48856 48875 AATATTAAACAATATGGACT  54  862 1101140 4332 4351 48858 48877 TTAATATTAAACAATATGGA  88  863 1101141 4334 4353 48860 48879 ACTTAATATTAAACAATATG 114  864 1101142 4335 4354 48861 48880 AACTTAATATTAAACAATAT  87  865 1101143 4343 4362 48869 48888 TTTTATTCAACTTAATATTA 100  866 1101144 4352 4371 48878 48897 TAAAATTTATTTTATTCAAC  99  867 1101145 4380 4399 48906 48925 CAAAATGTGATTTAGGCTCT  34  868 1101146 4389 4408 48915 48934 TCAGACAATCAAAATGTGAT  44  869 1101147 4397 4416 48923 48942 TCAAAAATTCAGACAATCAA  85  870 1101148 4399 4418 48925 48944 TATCAAAAATTCAGACAATC  74  871 1101149 4400 4419 48926 48945 GTATCAAAAATTCAGACAAT  71  872 1101151 4403 4422 48929 48948 ATAGTATCAAAAATTCAGAC  84  873 1101153 4758 4777 49284 49303 GGTTTTAAGAATTTAGTAGC  26  874 1101154 4759 4778 49285 49304 CGGTTTTAAGAATTTAGTAG  57  875 1101155 4762 4781 49288 49307 GGCCGGTTTTAAGAATTTAG  74  876 1101156 4793 4812 49319 49338 GAATCTATTTTTTATCTGTA  33  877 1101157 4820 4839 49346 49365 AAAATTATCATATTTTGATT  76  878 1101158 4821 4840 49347 49366 TAAAATTATCATATTTTGAT  97  879 1101159 4827 4846 49353 49372 AGATTTTAAAATTATCATAT  79  880 1101160 4831 4850 49357 49376 CTTAAGATTTTAAAATTATC  94  881 1101161 4834 4853 49360 49379 CTACTTAAGATTTTAAAATT 116  882 1101162 4841 4860 49367 49386 TATTTTTCTACTTAAGATTT  81  883 1101163 4843 4862 49369 49388 TTTATTTTTCTACTTAAGAT 130  884 1101164 4845 4864 49371 49390 GATTTATTTTTCTACTTAAG  85  885 1101165 4850 4869 49376 49395 ATCAAGATTTATTTTTCTAC  54  886 1101166 4851 4870 49377 49396 CATCAAGATTTATTTTTCTA  79  887 1101167 4853 4872 49379 49398 AACATCAAGATTTATTTTTC  90  888 1101168 4859 4878 49385 49404 ATTTAAAACATCAAGATTTA  98  889 1101169 4864 4883 49390 49409 TAAGAATTTAAAACATCAAG  63  890 1101170 4865 4884 49391 49410 GTAAGAATTTAAAACATCAA  76  891 1101171 4887 4906 49413 49432 CAATATTAACTATTGAATCC  88  892 1101172 5256 5275 49782 49801 ATAAAGTTTTTAATAGGAAG  99  893 1101173 5258 5277 49784 49803 GGATAAAGTTTTTAATAGGA  52  894 1101174 5556 5575 50082 50101 CAAACAAACCTTTAAGATGG  95  895 1101175 5557 5576 50083 50102 ACAAACAAACCTTTAAGATG  93  896 1101176 5575 5594 50101 50120 TTTCCGGATTAAAAAAAAAC 103  897 1101177 5801 5820 50327 50346 AAAAAAAACAAATATTCGCC  88  898 1101178 5802 5821 50328 50347 TAAAAAAAACAAATATTCGC 101  899 1101179 5947 5966 50473 50492 AAACAATTCACTTTGAAAAC  74  900 1101180 5950 5969 50476 50495 AACAAACAATTCACTTTGAA  62  901 1101181 5951 5970 50477 50496 CAACAAACAATTCACTTTGA  67  902 1101182 5952 5971 50478 50497 ACAACAAACAATTCACTTTG  44  903 1101183 5953 5972 50479 50498 TACAACAAACAATTCACTTT 102  904 1101184 5954 5973 50480 50499 ATACAACAAACAATTCACTT  63  905 1101185 5955 5974 50481 50500 GATACAACAAACAATTCACT  56  906 1101187 5958 5977 50484 50503 CTCGATACAACAAACAATTC  63  907 1101189 5960 5979 50486 50505 GACTCGATACAACAAACAAT  54  908 1101190 5961 5980 50487 50506 GGACTCGATACAACAAACAA  63  909 1101191 5962 5981 50488 50507 AGGACTCGATACAACAAACA  41  910 1101192 5963 5982 50489 50508 AAGGACTCGATACAACAAAC  38  911 1101193 5965 5984 50491 50510 TTAAGGACTCGATACAACAA  55  912 1101194 5976 5995 50502 50521 TATATCCATACTTAAGGACT  70  913 1101195 5986 6005 50512 50531 GGGTCACATATATATCCATA  71  914 1101196 5988 6007 50514 50533 TAGGGTCACATATATATCCA  51  915 1101197 5992 6011 50518 50537 TAATTAGGGTCACATATATA  98  916 1101198 5994 6013 50520 50539 CTTAATTAGGGTCACATATA  46  917 1101199 5995 6014 50521 50540 TCTTAATTAGGGTCACATAT  35  918 1101200 5996 6015 50522 50541 TTCTTAATTAGGGTCACATA  45  919 1101201 5997 6016 50523 50542 GTTCTTAATTAGGGTCACAT  20  920 1101202 5998 6017 50524 50543 AGTTCTTAATTAGGGTCACA  18  921 1101203 5999 6018 50525 50544 TAGTTCTTAATTAGGGTCAC  20  922 1101204 6000 6019 50526 50545 GTAGTTCTTAATTAGGGTCA  21  923 1101205 6002 6021 50528 50547 TGGTAGTTCTTAATTAGGGT  25  924 1101206 6018 6037 50544 50563 ATTAGTTGATCCAATCTGGT  52  925 1101207 6019 6038 50545 50564 GATTAGTTGATCCAATCTGG  40  926 1101208 6028 6047 50554 50573 TGCTGACATGATTAGTTGAT  41  927 1101209 6029 6048 50555 50574 TTGCTGACATGATTAGTTGA  51  928 1101210 6032 6051 50558 50577 ACATTGCTGACATGATTAGT  54  929 1101211 6041 6060 50567 50586 AAGTTATTTACATTGCTGAC  34  930 1101212 6044 6063 50570 50589 ATAAAGTTATTTACATTGCT  72  931 1101213 6045 6064 50571 50590 AATAAAGTTATTTACATTGC  86  932 1101214 6056 6075 50582 50601 TGAATATGAAAAATAAAGTT 112  933 1101215 6067 6086 50593 50612 AGTTTTTATTTTGAATATGA  75  934 1101216 6071 6090 50597 50616 AGAAAGTTTTTATTTTGAAT  99  935 1101217 6121 6140 50647 50666 GTCATTTTTTAAAGCAAAAA 110  936 1101218 6124 6143 50650 50669 CAGGTCATTTTTTAAAGCAA  32  937 1101219 6135 6154 50661 50680 AAATACAAAGCCAGGTCATT  64  938 1101220 6141 6160 50667 50686 CTAAAAAAATACAAAGCCAG 111  939 1101221 6142 6161 50668 50687 ACTAAAAAAATACAAAGCCA  55  940 1101223 6151 6170 50677 50696 ATGTTTAAGACTAAAAAAAT  90  941 1101225 6201 6220 50727 50746 GTCAATAATCTTCACTCATG  47  942 1101226 6205 6224 50731 50750 CGATGTCAATAATCTTCACT  71  943 1101227 6214 6233 50740 50759 ATTTACCAACGATGTCAATA  58  944 1101228 6216 6235 50742 50761 GAATTTACCAACGATGTCAA  58  945 1101229 6219 6238 50745 50764 CTAGAATTTACCAACGATGT  49  946 1101230 6223 6242 50749 50768 AATTCTAGAATTTACCAACG  57  947 1101231 6224 6243 50750 50769 AAATTCTAGAATTTACCAAC  63  948 1101232 6225 6244 50751 50770 AAAATTCTAGAATTTACCAA 101  949 1101233 6228 6247 50754 50773 ATCAAAATTCTAGAATTTAC  85  950 1101234 6230 6249 50756 50775 AAATCAAAATTCTAGAATTT  95  951 1101235 6232 6251 50758 50777 CAAAATCAAAATTCTAGAAT 107  952 1101236 6301 6320 50827 50846 ACTAATTCTTAAAATGCCAG  66  953 1101237 6302 6321 50828 50847 CACTAATTCTTAAAATGCCA  64  954 1101238 6332 6351 50858 50877 TTACGACAAATTTAGAAGTT 100  955 1101239 6341 6360 50867 50886 ACATGCCAATTACGACAAAT  65  956 1101240 6351 6370 50877 50896 ATGCTATTAAACATGCCAAT  52  957 1101241 6353 6372 50879 50898 ATATGCTATTAAACATGCCA  28  958 1101242 6354 6373 50880 50899 GATATGCTATTAAACATGCC  75  959 1101243 6355 6374 50881 50900 TGATATGCTATTAAACATGC  63  960 1101244 6363 6382 50889 50908 ATGTTTTTTGATATGCTATT  60  961 1101245 6364 6383 50890 50909 AATGTTTTTTGATATGCTAT  38  962 1101246 6365 6384 50891 50910 AAATGTTTTTTGATATGCTA  69  963 1101247 6366 6385 50892 50911 AAAATGTTTTTTGATATGCT  75  964 1101248 6376 6395 50902 50921 CCACAGGCTTAAAATGTTTT  87  965 1101249 6384 6403 50910 50929 CTATGAATCCACAGGCTTAA  47  966 1101250 6406 6425 50932 50951 CTAATGTTTCTCATTGCTTT  48  967 1101251 6420 6439 50946 50965 CCATTTATATTTTACTAATG  91  968 1101252 6423 6442 50949 50968 TATCCATTTATATTTTACTA  59  969 1101253 6427 6446 50953 50972 GGAATATCCATTTATATTTT  53  970 1101254 6447 6466 50973 50992 AGAGCTTCCTAAATGCATCA  62  971 1101255 6480 6499 51006 51025 AAAACATTCCTTGAACTATG  71  972 1101256 6482 6501 51008 51027 AGAAAACATTCCTTGAACTA  71  973 1101257 6484 6503 51010 51029 TCAGAAAACATTCCTTGAAC  77  974 1101259 6546 6565 51072 51091 GATAATCACATTTAAAAATG  82  975 1101261 6552 6571 51078 51097 AAATTAGATAATCACATTTA 107  976 1101262 6553 6572 51079 51098 AAAATTAGATAATCACATTT  95  977 1101263 6554 6573 51080 51099 AAAAATTAGATAATCACATT 112  978 1101264 6555 6574 51081 51100 TAAAAATTAGATAATCACAT  81  979 1101265 6557 6576 51083 51102 TGTAAAAATTAGATAATCAC 103  980 1101266 6560 6579 51086 51105 TGTTGTAAAAATTAGATAAT 119  981 1101267 6561 6580 51087 51106 GTGTTGTAAAAATTAGATAA  73  982 1101268 6562 6581 51088 51107 AGTGTTGTAAAAATTAGATA  88  983 1101269 6563 6582 51089 51108 CAGTGTTGTAAAAATTAGAT  81  984 1101270 6571 6590 51097 51116 TAATAGCCCAGTGTTGTAAA  46  985 1101271 6573 6592 51099 51118 CCTAATAGCCCAGTGTTGTA  39  986 1101272 6574 6593 51100 51119 TCCTAATAGCCCAGTGTTGT  48  987 1101273 6575 6594 51101 51120 TTCCTAATAGCCCAGTGTTG  49  988 1101274 6580 6599 51106 51125 AGTTATTCCTAATAGCCCAG  38  989 1101275 6581 6600 51107 51126 AAGTTATTCCTAATAGCCCA  56  990 1101276 6582 6601 51108 51127 AAAGTTATTCCTAATAGCCC  52  991 1101277 6583 6602 51109 51128 AAAAGTTATTCCTAATAGCC  60  992 1101278 6584 6603 51110 51129 AAAAAGTTATTCCTAATAGC  81  993 1101279 6585 6604 51111 51130 TAAAAAGTTATTCCTAATAG  78  994 1101280 6587 6606 51113 51132 TTTAAAAAGTTATTCCTAAT 108  995 1101281 6600 6619 51126 51145 CAGAACAGTAATTTTTAAAA 106  996 1101282 6604 6623 51130 51149 TATACAGAACAGTAATTTTT  64  997 1101283 6605 6624 51131 51150 TTATACAGAACAGTAATTTT  85  998 1101284 6606 6625 51132 51151 TTTATACAGAACAGTAATTT  95  999 1101285 6607 6626 51133 51152 ATTTATACAGAACAGTAATT 104 1000 1101286 6612 6631 51138 51157 CAAATATTTATACAGAACAG  78 1001 1101287 6614 6633 51140 51159 TTCAAATATTTATACAGAAC  70 1002 1101288 6615 6634 51141 51160 TTTCAAATATTTATACAGAA  42 1003 1101289 6616 6635 51142 51161 ATTTCAAATATTTATACAGA  87 1004 1101290 6618 6637 51144 51163 GAATTTCAAATATTTATACA  97 1005 1101291 6621 6640 51147 51166 CTTGAATTTCAAATATTTAT  94 1006 1101292 6636 6655 51162 51181 CAGATATTTTCTGTACTTGA  32 1007 1101293 6645 6664 51171 51190 TTTTTGTTTCAGATATTTTC  82 1008 1101295 6661 6680 51187 51206 GGCCAAACAACAATGCTTTT  72 1009 1101297 6664 6683 51190 51209 CATGGCCAAACAACAATGCT  83 1010 1101298 6665 6684 51191 51210 TCATGGCCAAACAACAATGC  80 1011 1101299 6667 6686 51193 51212 TATCATGGCCAAACAACAAT  76 1012 1101300 6674 6693 51200 51219 GCACTTGTATCATGGCCAAA  50 1013 1101301 6675 6694 51201 51220 TGCACTTGTATCATGGCCAA  64 1014 1101302 6750 6769 51276 51295 AGCAAATGAACTTAACGAGG  32 1015 1101303 6756 6775 51282 51301 AATAACAGCAAATGAACTTA  64 1016 1101304 6762 6781 51288 51307 GTGTGTAATAACAGCAAATG  52 1017 1101305 6764 6783 51290 51309 GTGTGTGTAATAACAGCAAA  81 1018 1101306 6765 6784 51291 51310 TGTGTGTGTAATAACAGCAA  65 1019 1101307 6798 6817 51324 51343 GCCCGGCTTTTCTAACGACC  77 1020 1101308 6839 6858 51365 51384 CACACTAACAACAGAATCCT  75 1021 1101309 6841 6860 51367 51386 TCCACACTAACAACAGAATC  94 1022 1101310 6842 6861 51368 51387 ATCCACACTAACAACAGAAT  72 1023 1101311 6844 6863 51370 51389 ACATCCACACTAACAACAGA  57 1024 1101312 6845 6864 51371 51390 AACATCCACACTAACAACAG  70 1025 1101313 6846 6865 51372 51391 GAACATCCACACTAACAACA  73 1026 1101314 6848 6867 51374 51393 TTGAACATCCACACTAACAA  73 1027 1101315 6851 6870 51377 51396 TCATTGAACATCCACACTAA  62 1028 1101316 6852 6871 51378 51397 CTCATTGAACATCCACACTA  70 1029 1101317 6853 6872 51379 51398 ACTCATTGAACATCCACACT  69 1030 1101318 6854 6873 51380 51399 AACTCATTGAACATCCACAC  67 1031 1101319 6860 6879 51386 51405 AAATACAACTCATTGAACAT  66 1032 1101320 6861 6880 51387 51406 AAAATACAACTCATTGAACA  88 1033 1101321 6862 6881 51388 51407 TAAAATACAACTCATTGAAC  81 1034 1101322 6863 6882 51389 51408 TTAAAATACAACTCATTGAA 102 1035 1101323 6865 6884 51391 51410 ATTTAAAATACAACTCATTG  73 1036 1101324 6867 6886 51393 51412 ATATTTAAAATACAACTCAT 101 1037 1101325 6868 6887 51394 51413 GATATTTAAAATACAACTCA  38 1038 1101326 6869 6888 51395 51414 TGATATTTAAAATACAACTC  83 1039 1101327 6870 6889 51396 51415 TTGATATTTAAAATACAACT  77 1040 1101328 6871 6890 51397 51416 TTTGATATTTAAAATACAAC  77 1041 1101329 6880 6899 51406 51425 TTAATAATCTTTGATATTTA 129 1042 1101331 6887 6906 51413 51432 TCTTTATTTAATAATCTTTG  80 1043 1101333 6891 6910 51417 51436 ATTATCTTTATTTAATAATC  91 1044 1101334 6895 6914 51421 51440 AAACATTATCTTTATTTAAT  79 1045 1101335 6902 6921 51428 51447 GAAAAGCAAACATTATCTTT  99 1046 1101336   90  109 N/A N/A AAAGTGAGCCTTCTTGTTTC  57 1047 1101337   92  111 N/A N/A ACAAAGTGAGCCTTCTTGTT  54 1048 1101338   93  112 N/A N/A CACAAAGTGAGCCTTCTTGT  62 1049 1101339   94  113 13163 13182 GCACAAAGTGAGCCTTCTTG  11 1050 1101340   95  114 13164 13183 AGCACAAAGTGAGCCTTCTT  35 1051 1101341   96  115 13165 13184 GAGCACAAAGTGAGCCTTCT 102 1052 1101342   97  116 13166 13185 TGAGCACAAAGTGAGCCTTC  75 1053 1101343   98  117 13167 13186 TTGAGCACAAAGTGAGCCTT  60 1054 1101344  100  119 13169 13188 TGTTGAGCACAAAGTGAGCC  45 1055 1101345  116  135 13185 13204 TAAGTTATTCAGGCAATGTT  35 1056 1101346  118  137 13187 13206 AATAAGTTATTCAGGCAATG  34 1057 1101347  136  155 13205 13224 CTAAAATATTCTCCTTGCAA  51 1058 1101348  137  156 13206 13225 GCTAAAATATTCTCCTTGCA  33 1059 1101349  138  157 13207 13226 GGCTAAAATATTCTCCTTGC  12 1060 1101350  152  171 13221 13240 GGATAATTCCACAGGGCTAA  13 1061 1101351  153  172 13222 13241 AGGATAATTCCACAGGGCTA   9 1062 1101352  154  173 13223 13242 GAGGATAATTCCACAGGGCT  12 1063 1101353  155  174 13224 13243 TGAGGATAATTCCACAGGGC  21 1064 1101354  156  175 13225 13244 TTGAGGATAATTCCACAGGG  21 1065 1101355  157  176 13226 13245 ATTGAGGATAATTCCACAGG  46 1066 1101356  158  177 13227 13246 AATTGAGGATAATTCCACAG  53 1067 1101357  183  202 13252 13271 TCTCCTCCTCATCCAGCTGA  54 1068 1101358  184  203 13253 13272 CTCTCCTCCTCATCCAGCTG  83 1069 1101359  186  205 13255 13274 TCCTCTCCTCCTCATCCAGC  28 1070 1101360  187  206 13256 13275 ATCCTCTCCTCCTCATCCAG  44 1071 1101361  189  208 13258 13277 TCATCCTCTCCTCCTCATCC  41 1072 1101362  193  212 13262 13281 ATTCTCATCCTCTCCTCCTC  37 1073 1101363  194  213 13263 13282 CATTCTCATCCTCTCCTCCT  49 1074 1101364  197  216 13266 13285 TGCCATTCTCATCCTCTCCT  15 1075 1101365  198  217 13267 13286 CTGCCATTCTCATCCTCTCC  26 1076 1101367  211  230 13280 13299 GTAACTCCTCCTTCTGCCAT  31 1077 1101369  214  233 13283 13302 CTAGTAACTCCTCCTTCTGC  35 1078 1101370  215  234 13284 13303 ACTAGTAACTCCTCCTTCTG  22 1079 1101371  217  236 13286 13305 TCACTAGTAACTCCTCCTTC  75 1080 1101372  218  237 13287 13306 TTCACTAGTAACTCCTCCTT  69 1081 1101373  220  239 13289 13308 TCTTCACTAGTAACTCCTCC  67 1082 1101374  225  244 13294 13313 GATAATCTTCACTAGTAACT  66 1083 1101375  227  246 13296 13315 GCGATAATCTTCACTAGTAA  35 1084 1101376  228  247 13297 13316 TGCGATAATCTTCACTAGTA  60 1085 1101377  229  248 13298 13317 GTGCGATAATCTTCACTAGT  97 1086 1101378  230  249 13299 13318 CGTGCGATAATCTTCACTAG  74 1087 1101379  248  267 N/A N/A AGAAGGCTGCTGTAAAAACG  44 1088 1101380  249  268 N/A N/A CAGAAGGCTGCTGTAAAAAC  51 1089 1101381  251  270 N/A N/A TCCAGAAGGCTGCTGTAAAA  51 1090 1101382  258  277 13863 13882 CCATATTTCCAGAAGGCTGC  35 1091 1101383  259  278 13864 13883 TCCATATTTCCAGAAGGCTG  21 1092 1101384  260  279 13865 13884 ATCCATATTTCCAGAAGGCT  15 1093 1101385  261  280 13866 13885 CATCCATATTTCCAGAAGGC  26 1094 1101386  262  281 13867 13886 TCATCCATATTTCCAGAAGG  56 1095 1101387  263  282 13868 13887 GTCATCCATATTTCCAGAAG  31 1096 1101388  266  285 13871 13890 ACTGTCATCCATATTTCCAG  23 1097 1101389  267  286 13872 13891 CACTGTCATCCATATTTCCA  61 1098 1101390  270  289 13875 13894 AACCACTGTCATCCATATTT  56 1099 1101391  275  294 13880 13899 GAAAAAACCACTGTCATCCA  40 1100 1101392  276  295 13881 13900 AGAAAAAACCACTGTCATCC  60 1101 1101393  278  297 13883 13902 AGAGAAAAAACCACTGTCAT  66 1102 1101394  279  298 13884 13903 TAGAGAAAAAACCACTGTCA  64 1103 1101395  281  300 13886 13905 AATAGAGAAAAAACCACTGT  83 1104 1101396  282  301 13887 13906 GAATAGAGAAAAAACCACTG  62 1105 1101397  283  302 13888 13907 TGAATAGAGAAAAAACCACT  68 1106 1101398  284  303 13889 13908 CTGAATAGAGAAAAAACCAC 115 1107 1101405  291  310 N/A N/A TTATAACCTGAATAGAGAAA 111 1108 1101406  293  312 N/A N/A GCTTATAACCTGAATAGAGA  39 1109 1101407  294  313 N/A N/A TGCTTATAACCTGAATAGAG  41 1110 1101408  295  314 N/A N/A TTGCTTATAACCTGAATAGA  57 1111 1101409  296  315 N/A N/A ATTGCTTATAACCTGAATAG  63 1112 1101410  298  317 N/A N/A GCATTGCTTATAACCTGAAT  43 1113 1101411  299  318 N/A N/A GGCATTGCTTATAACCTGAA  11 1114 1101412 N/A N/A 51448 51467 CACAAATTCAAAAGGAAATA 109 1115 1101413 N/A N/A 51449 51468 ACACAAATTCAAAAGGAAAT  83 1116 1101414 N/A N/A 51451 51470 AAACACAAATTCAAAAGGAA  92 1117 1101415 N/A N/A 51452 51471 TAAACACAAATTCAAAAGGA  91 1118 1101416 N/A N/A 51459 51478 TTAACAATAAACACAAATTC  79 1119 1101417 N/A N/A 51464 51483 ATGAATTAACAATAAACACA 155 1120 1101418 N/A N/A 51465 51484 TATGAATTAACAATAAACAC 101 1121 1101419 N/A N/A 51466 51485 CTATGAATTAACAATAAACA 107 1122 1101420 N/A N/A 51469 51488 TAGCTATGAATTAACAATAA  99 1123 1101421 N/A N/A 51471 51490 AATAGCTATGAATTAACAAT  70 1124 1101422 N/A N/A 51857 51876 AATAGAATATCAATGGACTG  65 1125 1101423 N/A N/A 51860 51879 TGGAATAGAATATCAATGGA  54 1126 1101424 N/A N/A 51862 51881 GCTGGAATAGAATATCAATG  52 1127 1101425 N/A N/A 51943 51962 TCAAATAAAAATTTGGAATT 108 1128 1101426 N/A N/A 51944 51963 TTCAAATAAAAATTTGGAAT  82 1129 1101427 N/A N/A 52274 52293 TCCTCAATCAGTCTAGGTGG  89 1130 1101428 N/A N/A 52275 52294 TTCCTCAATCAGTCTAGGTG  92 1131 1101429 N/A N/A 52281 52300 AATATATTCCTCAATCAGTC 114 1132 1101430 N/A N/A 52282 52301 CAATATATTCCTCAATCAGT  90 1133 1101431 N/A N/A 52283 52302 ACAATATATTCCTCAATCAG 112 1134 1101432 N/A N/A 52338 52357 GTGCCCAATCCTAATTAAAG 130 1135 1101433 N/A N/A 52339 52358 TGTGCCCAATCCTAATTAAA  97 1136 1101434 N/A N/A 52352 52371 ATGTTTCAAAATTTGTGCCC  64 1137 1101435 N/A N/A 52354 52373 TTATGTTTCAAAATTTGTGC  89 1138 1101436 N/A N/A 52355 52374 ATTATGTTTCAAAATTTGTG  81 1139 1101437 N/A N/A 53333 53352 ACCCTAATACAAGAGACTCT 110 1140 1101439 N/A N/A 53336 53355 TCTACCCTAATACAAGAGAC 100 1141 1101441 N/A N/A 53779 53798 CCATGTAGTGACATGTGGCT  87 1142 1101442 N/A N/A 53929 53948 TTTTGGAAAAAATGGATCTG  93 1143 1101443 N/A N/A 53930 53949 CTTTTGGAAAAAATGGATCT  88 1144 1101444 N/A N/A 53931 53950 GCTTTTGGAAAAAATGGATC  82 1145 1101445 N/A N/A 53944 53963 GAATTCAAACACAGCTTTTG  90 1146 1101446 N/A N/A 53948 53967 TGCAGAATTCAAACACAGCT  82 1147 1101447 N/A N/A 53951 53970 CTGTGCAGAATTCAAACACA  66 1148 1101574 N/A N/A  3683  3702 GCCCATACTCCCTCCCGGCT 106 1149 1101575 N/A N/A  3690  3709 CGGCCCCGCCCATACTCCCT 101 1150 1101576 N/A N/A  3740  3759 AGAAGCAAACCCACTGGGCG  96 1151 1101577 N/A N/A  3885  3904 GAAAAGTTAATTCTGCCAGG  49 1152 1101578 N/A N/A  3948  3967 ACAAGACCCCAAAGATCTAC  71 1153 1101579 N/A N/A  4012  4031 AGTGGGCGAGCCAAGGTCTC  87 1154 1101580 N/A N/A  4093  4112 GTAATAAAAACTCTTGTGAC  61 1155 1101581 N/A N/A  4109  4128 CAAACCCAAACATCCCGTAA 135 1156 1101583 N/A N/A  4113  4132 AAACCAAACCCAAACATCCC  80 1157 1101585 N/A N/A  4128  4147 TGGGAGTACCAAAAGAAACC  71 1158 1101586 N/A N/A  4165  4184 TACCTAAAAACAAAGCTGGC  86 1159 1101587 N/A N/A  4166  4185 ATACCTAAAAACAAAGCTGG  69 1160 1101588 N/A N/A  4168  4187 TAATACCTAAAAACAAAGCT  90 1161 1101589 N/A N/A  4170  4189 CCTAATACCTAAAAACAAAG 102 1162 1101590 N/A N/A  4171  4190 TCCTAATACCTAAAAACAAA  95 1163 1101591 N/A N/A  4172  4191 CTCCTAATACCTAAAAACAA  81 1164 1101592 N/A N/A  4173  4192 ACTCCTAATACCTAAAAACA  85 1165 1101593 N/A N/A  4174  4193 CACTCCTAATACCTAAAAAC  83 1166 1101594 N/A N/A  4175  4194 CCACTCCTAATACCTAAAAA 117 1167 1101595 N/A N/A  4180  4199 CCAGTCCACTCCTAATACCT  63 1168 1101596 N/A N/A  4194  4213 ACAACAAAATCATCCCAGTC  77 1169 1101597 N/A N/A  4195  4214 TACAACAAAATCATCCCAGT  71 1170 1101598 N/A N/A  4254  4273 AACAGTATCTTCAAGTGCAT  53 1171 1101599 N/A N/A  4255  4274 AAACAGTATCTTCAAGTGCA  52 1172 1101600 N/A N/A  4277  4296 GAGGAGTTTCTTTACATATC  13 1173 1101601 N/A N/A  4357  4376 AACATGATACCATGTGCCAA  27 1174 1101602 N/A N/A  4375  4394 AACACGAAACTATTATGAAA  88 1175 1101603 N/A N/A  4415  4434 TCCTCCTATTAAATAACAGC  62 1176 1101604 N/A N/A  4421  4440 CTTTGCTCCTCCTATTAAAT  55 1177 1101605 N/A N/A  4459  4478 TAAATGATCATTTATAAGTA 100 1178 1101606 N/A N/A  4481  4500 TGTGAATTTTAAATGTCTGG  30 1179 1101607 N/A N/A  4482  4501 GTGTGAATTTTAAATGTCTG  19 1180 1101608 N/A N/A  4483  4502 TGTGTGAATTTTAAATGTCT  45 1181 1101609 N/A N/A  4484  4503 GTGTGTGAATTTTAAATGTC  35 1182 1101610 N/A N/A  4728  4747 TCTCCCAAAAACATTACCTG 179 1183 1101611 N/A N/A  4732  4751 CGTCTCTCCCAAAAACATTA  88 1184 1101612 N/A N/A  4857  4876 GTACTTAACAATTTGTTCCA  46 1185 1101613 N/A N/A  4858  4877 TGTACTTAACAATTTGTTCC  47 1186 1101614 N/A N/A  4864  4883 AAGCATTGTACTTAACAATT  55 1187 1101615 N/A N/A  4884  4903 GAGATGTTTTCTACAATGAA  26 1188 1101616 N/A N/A  4903  4922 GCCTATTTCAAAAGTTTCCG  42 1189 1101617 N/A N/A  4904  4923 AGCCTATTTCAAAAGTTTCC  59 1190 1101619 N/A N/A  4949  4968 TAGTGACAACTATACGACTG  53 1191 1101621 N/A N/A  5009  5028 CCAAGCAACCAAATCTCTAT  67 1192 1101622 N/A N/A  5351  5370 ATAACAAAAATATGGCCGGG  91 1193 1101623 N/A N/A  5352  5371 AATAACAAAAATATGGCCGG  91 1194 1101624 N/A N/A  5353  5372 TAATAACAAAAATATGGCCG 101 1195 1101625 N/A N/A  5354  5373 TTAATAACAAAAATATGGCC  85 1196 1101626 N/A N/A  5355  5374 ATTAATAACAAAAATATGGC 163 1197 1101627 N/A N/A  5356  5375 AATTAATAACAAAAATATGG  83 1198 1101628 N/A N/A  5363  5382 CTTTGAAAATTAATAACAAA 115 1199 1101629 N/A N/A  5365  5384 GCCTTTGAAAATTAATAACA  85 1200 1101630 N/A N/A  5378  5397 GTCCCACACCAAAGCCTTTG  73 1201 1101631 N/A N/A  5452  5471 ATATTGTTAAAAATCTTGTC  72 1202 1101632 N/A N/A  5454  5473 CAATATTGTTAAAAATCTTG  79 1203 1101633 N/A N/A  5959  5978 AAAAACTAAATTGTTGAATC  98 1204 1101634 N/A N/A  5962  5981 CCAAAAAACTAAATTGTTGA  77 1205 1101635 N/A N/A  5964  5983 GCCCAAAAAACTAAATTGTT  98 1206 1101636 N/A N/A  5965  5984 CGCCCAAAAAACTAAATTGT  87 1207 1101637 N/A N/A  6050  6069 CACAGTAAGCCCAAACATTC  85 1208 1101638 N/A N/A  6102  6121 AGCAAGGGTTAAAGGTATAT  68 1209 1101639 N/A N/A  6121  6140 CTCTCCAAACCCAGGACCTA 115 1210 1101640 N/A N/A  6147  6166 CTTTAGGGCCAAAGTTGGTT  70 1211 1101641 N/A N/A  6156  6175 ACACAGCTTCTTTAGGGCCA  56 1212 1101642 N/A N/A  6212  6231 CCAAGGTTCCAAGAGGAAAT  60 1213 1101643 N/A N/A  6221  6240 AAGAGGAAACCAAGGTTCCA  94 1214 1101644 N/A N/A  6247  6266 AAGGGTACTCAAAGTGACTA  69 1215 1101645 N/A N/A  6264  6283 TACATTCTAACTTAATAAAG  93 1216 1101646 N/A N/A  6269  6288 GTTTTTACATTCTAACTTAA  65 1217 1101647 N/A N/A  6274  6293 AAACTGTTTTTACATTCTAA  64 1218 1101648 N/A N/A  6275  6294 GAAACTGTTTTTACATTCTA  58 1219 1101649 N/A N/A  6348  6367 GCCCCATTCAAATATTTATT 137 1220 1101650 N/A N/A  6558  6577 TCCATTCAAATATATACATT  74 1221 1101651 N/A N/A  6561  6580 TTATCCATTCAAATATATAC  90 1222 1101652 N/A N/A  6565  6584 CTCTTTATCCATTCAAATAT  70 1223 1101653 N/A N/A  6566  6585 TCTCTTTATCCATTCAAATA  79 1224 1101655 N/A N/A  6593  6612 CATATATATCTCAGAAACTC  62 1225 1101657 N/A N/A  6597  6616 GCACCATATATATCTCAGAA  15 1226 1101658 N/A N/A  6598  6617 AGCACCATATATATCTCAGA  25 1227 1101659 N/A N/A  6599  6618 CAGCACCATATATATCTCAG  21 1228 1101660 N/A N/A  6601  6620 AACAGCACCATATATATCTC  54 1229 1101661 N/A N/A  6610  6629 CTTTAGATAAACAGCACCAT  66 1230 1101662 N/A N/A  6614  6633 TTTACTTTAGATAAACAGCA  56 1231 1101663 N/A N/A  6639  6658 CCTTAAAATATTTACAGAAA  78 1232 1101664 N/A N/A  6648  6667 CCTGCAAAGCCTTAAAATAT  92 1233 1101665 N/A N/A  6667  6686 TGACAGAGACTACAGCTGGC  85 1234 1101666 N/A N/A  6698  6717 GTTGGGAAAAACATGCACAA  43 1235 1101667 N/A N/A  6700  6719 TGGTTGGGAAAAACATGCAC  34 1236 1101668 N/A N/A  6716  6735 ACTTTACATTTTTACATGGT  25 1237 1101669 N/A N/A  6731  6750 AGTAGCTAAGAATGCACTTT  74 1238 1101670 N/A N/A  6754  6773 ATGGGCCAAATTCAACCTGC  90 1239 1101671 N/A N/A  6824  6843 CAACAAAAATCCAGTAGTGG  68 1240 1101672 N/A N/A  6825  6844 ACAACAAAAATCCAGTAGTG  68 1241 1101673 N/A N/A  6842  6861 CAGAACTAAAACAAACAACA  78 1242 1101674 N/A N/A  6844  6863 ACCAGAACTAAAACAAACAA  92 1243 1101675 N/A N/A  6845  6864 CACCAGAACTAAAACAAACA 106 1244 1101676 N/A N/A  6847  6866 GGCACCAGAACTAAAACAAA  67 1245 1101677 N/A N/A  6851  6870 AGCAGGCACCAGAACTAAAA  74 1246 1101678 N/A N/A  6903  6922 TAACTGCACCAAGAAACATC  93 1247 1101679 N/A N/A  6924  6943 GCACCAATACAAATGGCACA  60 1248 1101680 N/A N/A  6926  6945 AAGCACCAATACAAATGGCA  69 1249 1101681 N/A N/A  6941  6960 TTTGCATTACATTAAAAGCA  64 1250 1101682 N/A N/A  6955  6974 GATATTATTACCAGTTTGCA  17 1251 1101683 N/A N/A  6977  6996 ATGTACAACCCCAGCAAGTT  41 1252 1101684 N/A N/A  6978  6997 TATGTACAACCCCAGCAAGT  73 1253 1101685 N/A N/A  6989  7008 TTCAATAATTTTATGTACAA  95 1254 1101686 N/A N/A  7037  7056 GGGCATAATGAATGCCACAG  75 1255 1101687 N/A N/A  7062  7081 TGGCTAAAATCCAGCAATCA  68 1256 1101688 N/A N/A  7093  7112 GGCTTCTCCTAAAGCTCAAA  73 1257 1101689 N/A N/A  7110  7129 TCATTTATACAGAATTTGGC  21 1258 1101691 N/A N/A  7120  7139 GCACTTCAAGTCATTTATAC  57 1259 1101693 N/A N/A  7304  7323 ACTATCTGCCAGGGAGCCTT  76 1260 1101694 N/A N/A  7328  7347 GGCAATGGCCAGTACTTCTA  79 1261 1101695 N/A N/A  7377  7396 TCTCCGAGCCCTTACTATGA  74 1262 1101696 N/A N/A  7462  7481 AGGTATAAACCTAAGGTGCT  58 1263 1101697 N/A N/A  7474  7493 ACAACACAAATCAGGTATAA  93 1264 1101698 N/A N/A  7477  7496 ACTACAACACAAATCAGGTA  80 1265 1101699 N/A N/A  7479  7498 TAACTACAACACAAATCAGG  73 1266 1101700 N/A N/A  7485  7504 CACTACTAACTACAACACAA  70 1267 1101701 N/A N/A  7486  7505 ACACTACTAACTACAACACA  91 1268 1101702 N/A N/A  7491  7510 CAGAGACACTACTAACTACA  66 1269 1101703 N/A N/A  7502  7521 GTTCAAATTACCAGAGACAC  75 1270 1101704 N/A N/A  7504  7523 TAGTTCAAATTACCAGAGAC  60 1271 1101705 N/A N/A  7505  7524 CTAGTTCAAATTACCAGAGA  66 1272 1101706 N/A N/A  7508  7527 AAACTAGTTCAAATTACCAG  84 1273 1101707 N/A N/A  7521  7540 CAAGACCAACCTGAAACTAG  70 1274 1101708 N/A N/A  7526  7545 GTTTTCAAGACCAACCTGAA 108 1275 1101709 N/A N/A  7549  7568 TCATTTACCCCCAACCTCCC  78 1276 1101710 N/A N/A  7552  7571 AAATCATTTACCCCCAACCT  81 1277 1101711 N/A N/A  7556  7575 TACCAAATCATTTACCCCCA  53 1278 1101712 N/A N/A  7558  7577 GCTACCAAATCATTTACCCC  82 1279 1101713 N/A N/A  7559  7578 TGCTACCAAATCATTTACCC  80 1280 1101714 N/A N/A  7562  7581 AACTGCTACCAAATCATTTA  53 1281 1101715 N/A N/A  7600  7619 GCAGTTCTACAAAGATAATG  46 1282 1101716 N/A N/A  8424  8443 ATTGAAATCTCATGATTTGG  92 1283 1101717 N/A N/A  8425  8444 TATTGAAATCTCATGATTTG  86 1284 1101718 N/A N/A  8447  8466 TGCCATAATCAAAGTTCAGC  29 1285 1101719 N/A N/A  8449  8468 TTTGCCATAATCAAAGTTCA  69 1286 1101720 N/A N/A  8453  8472 TCACTTTGCCATAATCAAAG  52 1287 1101721 N/A N/A  8455  8474 GTTCACTTTGCCATAATCAA  26 1288 1101722 N/A N/A  8474  8493 AGCTTTAATCAAAGCAGAAG  86 1289 1101723 N/A N/A  8477  8496 TCAAGCTTTAATCAAAGCAG 106 1290 1101724 N/A N/A  8504  8523 TCAAACTATCCCCAGCCACC 107 1291 1101725 N/A N/A  8508  8527 TATCTCAAACTATCCCCAGC 108 1292 1101727 N/A N/A  8510  8529 CTTATCTCAAACTATCCCCA 123 1293 1101729 N/A N/A  8514  8533 TGCCCTTATCTCAAACTATC 104 1294 1101730 N/A N/A  8520  8539 CTGCCTTGCCCTTATCTCAA  79 1295 1101731 N/A N/A  8531  8550 TATGCATTTTCCTGCCTTGC  71 1296 1101732 N/A N/A  8571  8590 ACCAAAAGAATTGTACAATG  85 1297 1101733 N/A N/A  8573  8592 GGACCAAAAGAATTGTACAA 106 1298 1101734 N/A N/A  8578  8597 CACATGGACCAAAAGAATTG 114 1299 1101735 N/A N/A  8591  8610 ACGGATCAAATTCCACATGG  51 1300 1101736 N/A N/A  8785  8804 TGGTTCATACTATAATCTCA  26 1301 1101737 N/A N/A  8823  8842 TCAGTACAAATTTAAAAATC  81 1302 1101738 N/A N/A  8826  8845 TGTTCAGTACAAATTTAAAA  76 1303 1101739 N/A N/A  8831  8850 CAAACTGTTCAGTACAAATT  71 1304 1101740 N/A N/A  8837  8856 AAAGGACAAACTGTTCAGTA  35 1305 1101741 N/A N/A  8860  8879 TTCTAATATGATTTAATGGA  94 1306 1101742 N/A N/A  8861  8880 CTTCTAATATGATTTAATGG  62 1307 1101743 N/A N/A  8882  8901 CAGGAAATATCAAGTTCTGT  47 1308 1101744 N/A N/A  8883  8902 ACAGGAAATATCAAGTTCTG  81 1309 1101745 N/A N/A  8903  8922 CAAAGAAAAACTGTATTGCT  53 1310 1101746 N/A N/A  8917  8936 AAATCAAACTTCATCAAAGA  90 1311 1101747 N/A N/A  8918  8937 GAAATCAAACTTCATCAAAG  52 1312 1101748 N/A N/A  8919  8938 TGAAATCAAACTTCATCAAA  86 1313 1101749 N/A N/A  8922  8941 ACTTGAAATCAAACTTCATC  57 1314 1101750 N/A N/A  8947  8966 TAGCTTTAAATTATGAAAAA  97 1315 1101751 N/A N/A  8948  8967 ATAGCTTTAAATTATGAAAA  64 1316 1101752 N/A N/A  8950  8969 AAATAGCTTTAAATTATGAA  99 1317 1101753 N/A N/A  8959  8978 CTCTATAAAAAATAGCTTTA 103 1318 1101754 N/A N/A  8973  8992 TTGATTAAAATTCTCTCTAT  97 1319 1101755 N/A N/A  8986  9005 GACATCCAAATATTTGATTA  33 1320 1101756 N/A N/A  8989  9008 AGTGACATCCAAATATTTGA  49 1321 1101757 N/A N/A  9010  9029 CTTAATACCATATATAGCAA  71 1322 1101758 N/A N/A  9012  9031 TACTTAATACCATATATAGC  73 1323 1101759 N/A N/A  9013  9032 ATACTTAATACCATATATAG 115 1324 1101760 N/A N/A  9023  9042 TATGGTCACCATACTTAATA  66 1325 1101761 N/A N/A  9033  9052 GTTTACAAACTATGGTCACC  78 1326 1101763 N/A N/A  9035  9054 GAGTTTACAAACTATGGTCA  58 1327 1101765 N/A N/A  9064  9083 CACAAATTTCCTGTCTTGCT  59 1328 1101766 N/A N/A  9068  9087 CTAACACAAATTTCCTGTCT  62 1329 1101767 N/A N/A  9071  9090 TTGCTAACACAAATTTCCTG  73 1330 1101768 N/A N/A  9073  9092 CTTTGCTAACACAAATTTCC  77 1331 1101769 N/A N/A  9083  9102 AGAAAAAAGCCTTTGCTAAC  95 1332 1101770 N/A N/A  9101  9120 TAAAAAATTCAAACAGTAAG  86 1333 1101771 N/A N/A  9319  9338 TCAGGCAAAACTCATTTATG  44 1334 1101772 N/A N/A  9340  9359 TCCAGTCACAAAAGCTCAAA  65 1335 1101773 N/A N/A  9341  9360 TTCCAGTCACAAAAGCTCAA  92 1336 1101774 N/A N/A  9389  9408 ATGGTAAACTAAAGAGGACA  88 1337 1101775 N/A N/A  9392  9411 ACAATGGTAAACTAAAGAGG  63 1338 1101776 N/A N/A  9400  9419 TTTCTCAAACAATGGTAAAC  50 1339 1101777 N/A N/A  9406  9425 GATAAATTTCTCAAACAATG 102 1340 1101778 N/A N/A  9447  9466 AATTAACAATAATTAACAGT  79 1341 1101779 N/A N/A  9450  9469 GTTAATTAACAATAATTAAC 103 1342 1101780 N/A N/A  9470  9489 ATGAATTAACTACAACAGTA 118 1343 1101781 N/A N/A  9500  9519 CTCACAAAAGAATACTAGAT  61 1344 1101782 N/A N/A  9507  9526 GTGTTTACTCACAAAAGAAT  65 1345 1101783 N/A N/A  9552  9571 GAAACGACCCAAATGGATAG  75 1346 1101784 N/A N/A  9554  9573 TGGAAACGACCCAAATGGAT  80 1347 1101785 N/A N/A  9585  9604 ATAGCATTACTATTTGTAAT  68 1348 1101786 N/A N/A  9597  9616 ATAGCATTACAGATAGCATT  40 1349 1101787 N/A N/A  9610  9629 GTAGTAATACAAAATAGCAT  85 1350 1101788 N/A N/A  9625  9644 ATAGCATTACTATTTGTAGT  68 1351 1101789 N/A N/A  9746  9765 ATCTCCTATGATCTAGCAAT  68 1352 1101790 N/A N/A  9761  9780 AAGCTTAATATATACATCTC  81 1353 1101791 N/A N/A  9763  9782 TAAAGCTTAATATATACATC 115 1354 1101792 N/A N/A  9788  9807 ACTAATAATTATGTAATGCA  98 1355 1101793 N/A N/A  9790  9809 TAACTAATAATTATGTAATG 126 1356 1101794 N/A N/A  9791  9810 ATAACTAATAATTATGTAAT  84 1357 1101795 N/A N/A  9792  9811 AATAACTAATAATTATGTAA 109 1358 1101796 N/A N/A  9797  9816 CCAATAATAACTAATAATTA  88 1359 1101797 N/A N/A  9798  9817 ACCAATAATAACTAATAATT 111 1360 1101799 N/A N/A  9806  9825 TTGGTATAACCAATAATAAC  85 1361 1101801 N/A N/A  9882  9901 CACAAACTCTAAAATGGCTA  72 1362 1101802 N/A N/A  9997 10016 GGCAAGACAAACAAGCACTT  77 1363 1101803 N/A N/A 10199 10218 CTTGAGCCCCAAAAAGGTCG  93 1364 1101804 N/A N/A 10409 10428 TGAAAAATAGCCAAGGCTGG  96 1365 1101805 N/A N/A 10424 10443 CTACTTATATCCTTTTGAAA  65 1366 1101806 N/A N/A 10439 10458 GGATATACAGATGTTCTACT  25 1367 1101807 N/A N/A 10441 10460 AGGGATATACAGATGTTCTA  39 1368 1101808 N/A N/A 10443 10462 GAAGGGATATACAGATGTTC  27 1369 1101809 N/A N/A 10463 10482 TACTGAATAATATGCAAATT  99 1370 1101810 N/A N/A 10468 10487 ACTCTTACTGAATAATATGC  75 1371 1101811 N/A N/A 10489 10508 TATTTCTACTACCAGAGTGC  38 1372 1101812 N/A N/A 10505 10524 CTTTCTCCTCCTTATATATT  67 1373 1101813 N/A N/A 10605 10624 AAGTTTATCTTCAACTTTTC  59 1374 1101814 N/A N/A 10606 10625 TAAGTTTATCTTCAACTTTT 101 1375 1101815 N/A N/A 10676 10695 GTGAAAAAAATATGGGTTAT  55 1376 1101816 N/A N/A 10677 10696 GGTGAAAAAAATATGGGTTA  37 1377 1101817 N/A N/A 10678 10697 TGGTGAAAAAAATATGGGTT  21 1378 1101818 N/A N/A 10679 10698 CTGGTGAAAAAAATATGGGT  57 1379 1101819 N/A N/A 10681 10700 AGCTGGTGAAAAAAATATGG  90 1380 1101820 N/A N/A 10683 10702 TCAGCTGGTGAAAAAAATAT  93 1381 1101821 N/A N/A 10694 10713 AGGAGCAAAATTCAGCTGGT  49 1382 1101822 N/A N/A 10745 10764 AAAGAGAACCACCTTGCAAG  87 1383 1101823 N/A N/A 10747 10766 CTAAAGAGAACCACCTTGCA  68 1384 1101824 N/A N/A 10809 10828 TTCCTTAACCCAACCTATCT 107 1385 1101825 N/A N/A 10810 10829 ATTCCTTAACCCAACCTATC  80 1386 1101826 N/A N/A 10815 10834 GGTCTATTCCTTAACCCAAC  53 1387 1101827 N/A N/A 10816 10835 AGGTCTATTCCTTAACCCAA  77 1388 1101828 N/A N/A 10817 10836 AAGGTCTATTCCTTAACCCA  42 1389 1101829 N/A N/A 10833 10852 TCTCTCTTTCCCCAATAAGG  75 1390 1101830 N/A N/A 10872 10891 AGAACATTTCCTTCTCCTGC  66 1391 1101831 N/A N/A 11044 11063 TGAATCCAAGTCCAGGGTGC  79 1392 1101832 N/A N/A 11071 11090 GGGCAGTTTCTCACACAACT  48 1393 1101833 N/A N/A 11185 11204 CCTGGACAAGCCAGCAAGAG 110 1394 1101835 N/A N/A 11215 11234 GAACTGTCCCAAACAACCCT  66 1395 1101837 N/A N/A 11258 11277 GGAACTCTACAGATAATGTA  66 1396 1101838 N/A N/A 11303 11322 GTTCCATGTTAAAACTTGCA 146 1397 1101839 N/A N/A 11308 11327 ATTCTGTTCCATGTTAAAAC 103 1398 1101840 N/A N/A 11317 11336 GTGAGAAAAATTCTGTTCCA  55 1399 1101841 N/A N/A 11320 11339 CAGGTGAGAAAAATTCTGTT 126 1400 1101842 N/A N/A 11370 11389 CACACAATCTAAATGCTTGT 102 1401 1101843 N/A N/A 11703 11722 CATTTATTCTTTTAACATGA  86 1402 1101844 N/A N/A 11707 11726 AGAACATTTATTCTTTTAAC 106 1403 1101845 N/A N/A 11711 11730 CCCTAGAACATTTATTCTTT  88 1404 1101846 N/A N/A 11870 11889 GAAAGGAAATTTTAGTCCCT  48 1405 1101847 N/A N/A 11879 11898 ACTAATGGTGAAAGGAAATT  89 1406 1101848 N/A N/A 11887 11906 AGTAAATTACTAATGGTGAA  51 1407 1101849 N/A N/A 11888 11907 CAGTAAATTACTAATGGTGA  63 1408 1101850 N/A N/A 11889 11908 ACAGTAAATTACTAATGGTG  59 1409 1101851 N/A N/A 11890 11909 TACAGTAAATTACTAATGGT  86 1410 1101852 N/A N/A 11925 11944 TTCAGTACCTAAAATAAGTT  86 1411 1101853 N/A N/A 11933 11952 CCCTCATTTTCAGTACCTAA  36 1412 1101854 N/A N/A 11951 11970 GTATAAAACATTTAGTCTCC  49 1413 1101855 N/A N/A 11952 11971 TGTATAAAACATTTAGTCTC  70 1414 1101856 N/A N/A 11953 11972 CTGTATAAAACATTTAGTCT  82 1415 1101857 N/A N/A 11954 11973 ACTGTATAAAACATTTAGTC  78 1416 1101858 N/A N/A 11977 11996 AATCTCATATTTTACTAAAA 127 1417 1101859 N/A N/A 11988 12007 CAAATGCATCAAATCTCATA  59 1418 1101860 N/A N/A 11997 12016 ATCATCTATCAAATGCATCA  38 1419 1101861 N/A N/A 12011 12030 TATTTTAAACAAACATCATC 107 1420 1101862 N/A N/A 12016 12035 AGAATTATTTTAAACAAACA 102 1421 1101863 N/A N/A 12017 12036 AAGAATTATTTTAAACAAAC  87 1422 1101864 N/A N/A 12027 12046 TCAAAAATTTAAGAATTATT  80 1423 1101865 N/A N/A 12028 12047 ATCAAAAATTTAAGAATTAT 130 1424 1101866 N/A N/A 12030 12049 TGATCAAAAATTTAAGAATT  73 1425 1101867 N/A N/A 12031 12050 ATGATCAAAAATTTAAGAAT 135 1426 1101868 N/A N/A 12032 12051 CATGATCAAAAATTTAAGAA  87 1427 1101869 N/A N/A 12034 12053 TACATGATCAAAAATTTAAG 120 1428 1101871 N/A N/A 12050 12069 TTAATGAAACTATAATTACA  96 1429 1101873 N/A N/A 12092 12111 CATGCATTTTCATTTGGTAA  21 1430 1101874 N/A N/A 12137 12156 TTGAACTGAACTTTCAGCTT  60 1431 1101875 N/A N/A 12268 12287 ATACGGTTTCACAATGTTAG  42 1432 1101876 N/A N/A 12770 12789 CTAAATAATTTAATCATTAA  91 1433 1101877 N/A N/A 12772 12791 CCCTAAATAATTTAATCATT 104 1434 1101878 N/A N/A 12774 12793 TCCCCTAAATAATTTAATCA 128 1435 1101879 N/A N/A 12778 12797 CGGCTCCCCTAAATAATTTA  81 1436 1101880 N/A N/A 13087 13106 ATCTTCCCCTAAATAATTTT  82 1437 1101881 N/A N/A 13129 13148 AGAAAAAATTAAAATGTGAC 106 1438 1101882 N/A N/A 13145 13164 TGCTAATATTTCCAAAAGAA  75 1439 1101883 N/A N/A 13146 13165 TTGCTAATATTTCCAAAAGA  61 1440 1101884 N/A N/A 13159 13178 AAAGTGAGCCTTCTTGCTAA  74 1441 1101885 N/A N/A 13328 13347 AGTGAGTTTAAAATCAGTAC  76 1442 1101886 N/A N/A 13329 13348 TAGTGAGTTTAAAATCAGTA  84 1443 1101887 N/A N/A 13664 13683 TATCCACATTTTTAAAAGAA  91 1444 1101888 N/A N/A 13709 13728 CAGTCAGATCCCTATAGGAA  31 1445 1101889 N/A N/A 13714 13733 TTCACCAGTCAGATCCCTAT  50 1446 1101890 N/A N/A 13718 13737 ATAATTCACCAGTCAGATCC  59 1447 1101891 N/A N/A 13720 13739 TTATAATTCACCAGTCAGAT  53 1448 1101892 N/A N/A 13721 13740 GTTATAATTCACCAGTCAGA  44 1449 1101893 N/A N/A 13722 13741 AGTTATAATTCACCAGTCAG  46 1450 1101894 N/A N/A 13723 13742 CAGTTATAATTCACCAGTCA  50 1451 1101895 N/A N/A 13724 13743 ACAGTTATAATTCACCAGTC  47 1452 1101896 N/A N/A 13746 13765 TCCCATTTCCAAAGTTAACA  62 1453 1101897 N/A N/A 13775 13794 GTGCATATTTAAAACAATAT 110 1454 1101898 N/A N/A 13796 13815 AGGATACAAACTGTCATTAG 141 1455 1101899 N/A N/A 13799 13818 AGAAGGATACAAACTGTCAT 106 1456 1101900 N/A N/A 13844 13863 CTGTTAATTTTGACAGGTAG  65 1457 1101901 N/A N/A 13847 13866 CTGCTGTTAATTTTGACAGG  96 1458 1101902 N/A N/A 13899 13918 GACTACTTACCTGAATAGAG  84 1459 1101903 N/A N/A 13904 13923 CTTGTGACTACTTACCTGAA  97 1460 1101904 N/A N/A 13926 13945 TGTAAGCAACACATAGTACA  98 1461 1101905 N/A N/A 14015 14034 GAGTATAATCTATACTCTGT 131 1462 1101907 N/A N/A 14331 14350 TATATAAAAATCTAGTACTC 111 1463 1101909 N/A N/A 14334 14353 ATCTATATAAAAATCTAGTA  75 1464 1101910 N/A N/A 14335 14354 TATCTATATAAAAATCTAGT  96 1465 1101911 N/A N/A 14343 14362 TTCATGTTTATCTATATAAA  82 1466 1101912 N/A N/A 14350 14369 CAATCCTTTCATGTTTATCT  25 1467 1101913 N/A N/A 14354 14373 TCTACAATCCTTTCATGTTT  47 1468 1101914 N/A N/A 14355 14374 TTCTACAATCCTTTCATGTT  43 1469 1101915 N/A N/A 14356 14375 ATTCTACAATCCTTTCATGT  41 1470 1101916 N/A N/A 14389 14408 AGGAATTTTTAAATGCCCCA  48 1471 1101917 N/A N/A 14390 14409 AAGGAATTTTTAAATGCCCC 104 1472 1101918 N/A N/A 14391 14410 GAAGGAATTTTTAAATGCCC  20 1473 1101919 N/A N/A 14392 14411 AGAAGGAATTTTTAAATGCC  52 1474 1101920 N/A N/A 14434 14453 TAAGGTTATTATTAGCATCC   8 1475 1101921 N/A N/A 14436 14455 ATTAAGGTTATTATTAGCAT  89 1476 1101922 N/A N/A 14792 14811 CTCAAATTTACCCAACAGAT  96 1477 1101923 N/A N/A 14796 14815 TTTTCTCAAATTTACCCAAC  77 1478 1101924 N/A N/A 14830 14849 GGCTGATTTAAAAGGATGGT  48 1479 1101925 N/A N/A 14831 14850 AGGCTGATTTAAAAGGATGG  57 1480 1101926 N/A N/A 14834 14853 GGTAGGCTGATTTAAAAGGA  25 1481 1101927 N/A N/A 14849 14868 AAGGAAATCCAGTCTGGTAG  27 1482 1101928 N/A N/A 14851 14870 ATAAGGAAATCCAGTCTGGT  78 1483 1101929 N/A N/A 14864 14883 GCCACAAACCATAATAAGGA  56 1484 1101930 N/A N/A 14873 14892 AAATCAAAAGCCACAAACCA  73 1485 1101931 N/A N/A 14895 14914 AGAGCTATACATTAAAAAAA  69 1486 1101932 N/A N/A 14909 14928 CAAAGAATTCAAAGAGAGCT  89 1487 1101933 N/A N/A 14914 14933 ACCACCAAAGAATTCAAAGA 119 1488 1101934 N/A N/A 14918 14937 TATAACCACCAAAGAATTCA  81 1489 1101935 N/A N/A 14921 14940 ATATATAACCACCAAAGAAT  84 1490 1101936 N/A N/A 14923 14942 ATATATATAACCACCAAAGA  95 1491 1101937 N/A N/A 14928 14947 TACATATATATATAACCACC  71 1492 1101938 N/A N/A 14930 14949 AGTACATATATATATAACCA  96 1493 1101939 N/A N/A 14949 14968 CAGATAAAAGAATCTTGCGA  84 1494 1101940 N/A N/A 14972 14991 TTAGAAAAAGAATGAAAGAC  27 1495 1101941 N/A N/A 14991 15010 CTGGATACAACTCACAGTGT  63 1496 1101943 N/A N/A 15141 15160 TGCAGTAGCCATTACCTGTT  87 1497 1101945 N/A N/A 15217 15236 AACAGGCACCAAGAGCAGCA  82 1498 1101946 N/A N/A 15292 15311 GGTAGCCAACAAAGAAGCAA  64 1499 1101947 N/A N/A 15295 15314 CAAGGTAGCCAACAAAGAAG  85 1500 1101948 N/A N/A 15297 15316 TCCAAGGTAGCCAACAAAGA  72 1501 1101949 N/A N/A 15318 15337 CTGAAAATTCACTATCTGCC  67 1502 1101950 N/A N/A 15321 15340 TTTCTGAAAATTCACTATCT  79 1503 1101951 N/A N/A 15324 15343 AAATTTCTGAAAATTCACTA  76 1504 1101952 N/A N/A 15367 15386 AAATGCAAACCTGTTTATTT  68 1505 1101953 N/A N/A 15441 15460 CTGGGCATTTAAACTGAAGG  72 1506 1101954 N/A N/A 15461 15480 TCTACCAAAATAAGTTCTCC  99 1507 1101955 N/A N/A 15465 15484 CATATCTACCAAAATAAGTT  76 1508 1101956 N/A N/A 15503 15522 AAAATTATATTCAACTTGCT  93 1509 1101957 N/A N/A 15519 15538 TGGGTGCTACTTTAGAAAAA  58 1510 1101958 N/A N/A 15552 15571 GTCTACTATATACATCTGAT  48 1511 1101959 N/A N/A 15555 15574 CTAGTCTACTATATACATCT  59 1512 1101960 N/A N/A 15556 15575 ACTAGTCTACTATATACATC  77 1513 1101961 N/A N/A 15561 15580 TTAAAACTAGTCTACTATAT  85 1514 1101962 N/A N/A 15585 15604 ATATTCTACCCATAAGTGCT  34 1515 1101963 N/A N/A 15588 15607 TGTATATTCTACCCATAAGT  66 1516 1101964 N/A N/A 15601 15620 TCAAAAATCCAGATGTATAT  98 1517 1101965 N/A N/A 15603 15622 CCTCAAAAATCCAGATGTAT  82 1518 1101966 N/A N/A 15604 15623 GCCTCAAAAATCCAGATGTA  98 1519 1101967 N/A N/A 15624 15643 CACAATTCCTAAATAAAACT 106 1520 1101968 N/A N/A 15626 15645 CACACAATTCCTAAATAAAA  89 1521 1101969 N/A N/A 15635 15654 CCAGAAAACCACACAATTCC  87 1522 1101970 N/A N/A 15636 15655 TCCAGAAAACCACACAATTC  83 1523 1101971 N/A N/A 15637 15656 TTCCAGAAAACCACACAATT  79 1524 1101972 N/A N/A 15640 15659 ATGTTCCAGAAAACCACACA  66 1525 1101973 N/A N/A 15643 15662 GAGATGTTCCAGAAAACCAC  43 1526 1101974 N/A N/A 15666 15685 AGTGCTTTTCATACCAGGTC   6 1527 1101975 N/A N/A 15667 15686 GAGTGCTTTTCATACCAGGT   6 1528 1101976 N/A N/A 15704 15723 CACTAAATCCATAAAAAAAA 110 1529 1101977 N/A N/A 15706 15725 ATCACTAAATCCATAAAAAA 101 1530 1101979 N/A N/A 15712 15731 AGATATATCACTAAATCCAT  51 1531 1101981 N/A N/A 15714 15733 ATAGATATATCACTAAATCC  63 1532 1101982 N/A N/A 15715 15734 TATAGATATATCACTAAATC 103 1533 1101983 N/A N/A 15719 15738 TGTGTATAGATATATCACTA  76 1534 1101984 N/A N/A 15720 15739 GTGTGTATAGATATATCACT  54 1535 1101985 N/A N/A 15739 15758 TATAGGTTTTAAAAAGTGTG  42 1536 1101986 N/A N/A 16063 16082 TATAAATTTCTCTAGAAGGC  58 1537 1101987 N/A N/A 16064 16083 ATATAAATTTCTCTAGAAGG  78 1538 1101988 N/A N/A 16068 16087 TCATATATAAATTTCTCTAG 102 1539 1101989 N/A N/A 16110 16129 CCATTCCAAATTTAGGAAGT  74 1540 1101990 N/A N/A 16113 16132 ACTCCATTCCAAATTTAGGA  60 1541 1101991 N/A N/A 16136 16155 AGCAACTTTTCATAAGCTAA  75 1542 1101992 N/A N/A 16160 16179 TGCTTATAACCTGTTAAGAA  28 1543 1101993 N/A N/A 16258 16277 GAAATGCAAAACAGAATCTT  70 1544 1101994 N/A N/A 16297 16316 TTACAACTTTAAAAATCAAA  72 1545 1101995 N/A N/A 16306 16325 TTTAAGAAATTACAACTTTA  89 1546 1101996 N/A N/A 16330 16349 AGTATTCAAAATGTATTTCT  80 1547 1101997 N/A N/A 16345 16364 GAACATCAAAACAAAAGTAT  86 1548 1101998 N/A N/A 16385 16404 CACAAAGGTGAAATAGGAAA  66 1549 1101999 N/A N/A 16529 16548 ATCACACAACCATATGAACG  70 1550 1102000 N/A N/A 16538 16557 TTTTAAAAGATCACACAACC  86 1551 1102001 N/A N/A 16540 16559 GTTTTTAAAAGATCACACAA  60 1552 1102002 N/A N/A 16543 16562 GATGTTTTTAAAAGATCACA  61 1553 1102003 N/A N/A 16546 16565 ACTGATGTTTTTAAAAGATC  45 1554 1102004 N/A N/A 16547 16566 CACTGATGTTTTTAAAAGAT  53 1555 1102005 N/A N/A 16571 16590 AAGATTATATTTATAGTTAA 121 1556 1102006 N/A N/A 16572 16591 TAAGATTATATTTATAGTTA  94 1557 1102007 N/A N/A 16581 16600 GTGATAATTTAAGATTATAT  51 1558 1102008 N/A N/A 16584 16603 TTTGTGATAATTTAAGATTA 125 1559 1102009 N/A N/A 16588 16607 AAAATTTGTGATAATTTAAG 136 1560 1102010 N/A N/A 16601 16620 GCAAATATTATATAAAATTT  85 1561 1102011 N/A N/A 16603 16622 TGGCAAATATTATATAAAAT  84 1562 1102012 N/A N/A 16627 16646 TGAATTCATATTTATGTTGT  54 1563 1102013 N/A N/A 16637 16656 CTTGAAATATTGAATTCATA  85 1564 1102015 N/A N/A 16655 16674 GAAAACAGACAATATTAACT  89 1565 1102017 N/A N/A 16680 16699 TAAATGATCTTTCATTTCTA  57 1566 1102018 N/A N/A 16732 16751 ACCTGTTTTCCTAATTTTCT  68 1567 1102019 N/A N/A 16748 16767 AAGGGTAAGAAATGTTACCT 113 1568 1102020 N/A N/A 16768 16787 TATAAGAAAAAAAGACAAGG 114 1569 1102021 N/A N/A 16771 16790 CAATATAAGAAAAAAAGACA  85 1570 1102022 N/A N/A 16800 16819 TGGCCCACATTTTAGTTTTA  91 1571 1102023 N/A N/A 17168 17187 AATTTTAAAGTCAGCAATCC  43 1572 1102024 N/A N/A 17172 17191 TCCTAATTTTAAAGTCAGCA   8 1573 1102025 N/A N/A 17173 17192 TTCCTAATTTTAAAGTCAGC 102 1574 1102026 N/A N/A 17174 17193 TTTCCTAATTTTAAAGTCAG  88 1575 1102027 N/A N/A 17175 17194 GTTTCCTAATTTTAAAGTCA  26 1576 1102028 N/A N/A 17180 17199 GGTCAGTTTCCTAATTTTAA   4 1577 1102029 N/A N/A 17237 17256 AATGACAATTTCTATCTATC  64 1578 1102030 N/A N/A 17252 17271 GATATTATCTTTTAAAATGA  88 1579 1102031 N/A N/A 17277 17296 CACAAATAAATTTATAAGGA 108 1580 1102032 N/A N/A 17283 17302 ACTTGTCACAAATAAATTTA 113 1581 1102033 N/A N/A 17284 17303 TACTTGTCACAAATAAATTT  77 1582 1102034 N/A N/A 17300 17319 ATAGTTAAATTGCATATACT  57 1583 1102035 N/A N/A 17304 17323 TGATATAGTTAAATTGCATA  51 1584 1102036 N/A N/A 17312 17331 TTTTCTTATGATATAGTTAA  70 1585 1102037 N/A N/A 17318 17337 TAGAATTTTTCTTATGATAT  78 1586 1102038 N/A N/A 17319 17338 ATAGAATTTTTCTTATGATA  83 1587 1102039 N/A N/A 17323 17342 TAATATAGAATTTTTCTTAT  94 1588 1102040 N/A N/A 17335 17354 TTGTATTATCTTTAATATAG  66 1589 1102041 N/A N/A 17365 17384 ACATAAAAACCCACTTAAAA  89 1590 1102042 N/A N/A 17369 17388 CATCACATAAAAACCCACTT  59 1591 1102043 N/A N/A 17378 17397 GAACATAGTCATCACATAAA  25 1592 1102044 N/A N/A 17380 17399 CAGAACATAGTCATCACATA  47 1593 1102045 N/A N/A 17417 17436 TGCTAAATACAAATCTATAA  97 1594 1102046 N/A N/A 17419 17438 TATGCTAAATACAAATCTAT 116 1595 1102047 N/A N/A 17420 17439 CTATGCTAAATACAAATCTA  94 1596 1102048 N/A N/A 17421 17440 ACTATGCTAAATACAAATCT  70 1597 1102049 N/A N/A 17446 17465 ACACTATTTCAGGCTTTGTG  15 1598 1102051 N/A N/A 17464 17483 ATGCTTTATTCATGCTTGAC  29 1599 1102053 N/A N/A 17494 17513 ATAATCTTACACTAAAGCAA  85 1600 1102054 N/A N/A 17497 17516 TGAATAATCTTACACTAAAG  86 1601 1102055 N/A N/A 17498 17517 ATGAATAATCTTACACTAAA  81 1602 1102056 N/A N/A 17505 17524 AATCATAATGAATAATCTTA  85 1603 1102057 N/A N/A 17576 17595 AGACATATTTCATGTTTTAT  40 1604 1102058 N/A N/A 17577 17596 AAGACATATTTCATGTTTTA  64 1605 1102059 N/A N/A 17578 17597 CAAGACATATTTCATGTTTT  56 1606 1102060 N/A N/A 17583 17602 TTGCTCAAGACATATTTCAT  30 1607 1102061 N/A N/A 17584 17603 CTTGCTCAAGACATATTTCA  84 1608 1102062 N/A N/A 17599 17618 TGTTTCTTAAAATAGCTTGC  33 1609 1102063 N/A N/A 17632 17651 TTCAAAATTCTAATAACAAG 104 1610 1102064 N/A N/A 17635 17654 AGATTCAAAATTCTAATAAC 121 1611 1102065 N/A N/A 17644 17663 CTCTTTCAAAGATTCAAAAT  72 1612 1102066 N/A N/A 17647 17666 ACCCTCTTTCAAAGATTCAA  64 1613 1102067 N/A N/A 17654 17673 TTCAATAACCCTCTTTCAAA  89 1614 1102068 N/A N/A 17779 17798 TAAATGATACCATACAGCAG  69 1615 1102069 N/A N/A 17783 17802 TTAATAAATGATACCATACA  79 1616 1102070 N/A N/A 17794 17813 TTTCTAGACTTTTAATAAAT  91 1617 1102071 N/A N/A 17941 17960 TACTACAACCAAGATAGTGA  93 1618 1102072 N/A N/A 17963 17982 TACTGTACTCCCATGAAACC  61 1619 1102073 N/A N/A 17971 17990 CATTTGTATACTGTACTCCC  28 1620 1102074 N/A N/A 18368 18387 TTGGCTTGTATTTACATTTT   6 1621 1102075 N/A N/A 18406 18425 AGATTTAATTCAATATATTT  79 1622 1102076 N/A N/A 18413 18432 CTCTTACAGATTTAATTCAA  49 1623 1102077 N/A N/A 18427 18446 TGTTTTTGAATTATCTCTTA  19 1624 1102078 N/A N/A 18448 18467 AAAAGATAACAATAGGGTTT  53 1625 1102079 N/A N/A 18449 18468 TAAAAGATAACAATAGGGTT  57 1626 1102080 N/A N/A 18452 18471 ACTTAAAAGATAACAATAGG  85 1627 1102081 N/A N/A 18454 18473 TGACTTAAAAGATAACAATA  88 1628 1102082 N/A N/A 18458 18477 TGGGTGACTTAAAAGATAAC  81 1629 1102083 N/A N/A 18461 18480 ATTTGGGTGACTTAAAAGAT  83 1630 1102084 N/A N/A 18478 18497 GACTTTTCCCAAATTTGATT  11 1631 1102085 N/A N/A 18480 18499 GTGACTTTTCCCAAATTTGA  18 1632 1102087 N/A N/A 18833 18852 TTAAGAAAGAACCAACTTAG  92 1633 1102089 N/A N/A 18844 18863 CAGGAAGAACTTTAAGAAAG  52 1634 1102090 N/A N/A 18875 18894 GTTACATCTCCTTAACTTGC  14 1635 1102091 N/A N/A 18903 18922 CCAGCTAGCCTCCACTGTAA  76 1636 1102092 N/A N/A 18905 18924 ACCCAGCTAGCCTCCACTGT 168 1637 1102093 N/A N/A 19119 19138 TTAAATAATCTCAGCAGTAC  43 1638 1102094 N/A N/A 19123 19142 GAGGTTAAATAATCTCAGCA  82 1639 1102095 N/A N/A 19124 19143 AGAGGTTAAATAATCTCAGC  67 1640 1102096 N/A N/A 19125 19144 CAGAGGTTAAATAATCTCAG  95 1641 1102097 N/A N/A 19126 19145 CCAGAGGTTAAATAATCTCA  98 1642 1102098 N/A N/A 19127 19146 CCCAGAGGTTAAATAATCTC  69 1643 1102099 N/A N/A 19135 19154 AAATAAAACCCAGAGGTTAA  79 1644 1102100 N/A N/A 19136 19155 TAAATAAAACCCAGAGGTTA  81 1645 1102101 N/A N/A 19137 19156 ATAAATAAAACCCAGAGGTT  85 1646 1102102 N/A N/A 19192 19211 GCTTACTTTATACAAAAAAA  65 1647 1102103 N/A N/A 19194 19213 GTGCTTACTTTATACAAAAA  17 1648 1102104 N/A N/A 19196 19215 CAGTGCTTACTTTATACAAA   4 1649 1102105 N/A N/A 19207 19226 CCTTAAAAATTCAGTGCTTA  31 1650 1102106 N/A N/A 19208 19227 ACCTTAAAAATTCAGTGCTT  29 1651 1102107 N/A N/A 19216 19235 TTAATACAACCTTAAAAATT  87 1652 1102108 N/A N/A 19222 19241 TGCAAATTAATACAACCTTA  17 1653 1102109 N/A N/A 19232 19251 GACATTTATTTGCAAATTAA  30 1654 1102110 N/A N/A 19238 19257 AAGATAGACATTTATTTGCA  12 1655 1102111 N/A N/A 19239 19258 TAAGATAGACATTTATTTGC  27 1656 1102112 N/A N/A 19241 19260 AATAAGATAGACATTTATTT 112 1657 1102113 N/A N/A 19246 19265 AAAATAATAAGATAGACATT 100 1658 1102114 N/A N/A 19249 19268 CTCAAAATAATAAGATAGAC 108 1659 1102115 N/A N/A 19250 19269 TCTCAAAATAATAAGATAGA  71 1660 1102116 N/A N/A 19251 19270 CTCTCAAAATAATAAGATAG 100 1661 1102117 N/A N/A 19265 19284 AAAATTTTTTAAATCTCTCA  97 1662 1102118 N/A N/A 19296 19315 TCAAAATGTGAAAATGCAAT  81 1663 1102119 N/A N/A 19340 19359 AACCAAAATTTGACATCTTC  23 1664 1102120 N/A N/A 19343 19362 ATAAACCAAAATTTGACATC  75 1665 1102121 N/A N/A 19346 19365 AAAATAAACCAAAATTTGAC 126 1666 1102123 N/A N/A 19393 19412 ATAGTGAAAAATATAGTTTT  91 1667 1102125 N/A N/A 19395 19414 CTATAGTGAAAAATATAGTT  92 1668 1102126 N/A N/A 19397 19416 GTCTATAGTGAAAAATATAG  90 1669 1102127 N/A N/A 19430 19449 TTCATTATACAGGGACCTCG  60 1670 1102128 N/A N/A 19437 19456 CTTCTTTTTCATTATACAGG  11 1671 1102129 N/A N/A 19453 19472 TAATACTTTTTCCAGCCTTC  17 1672 1102130 N/A N/A 19455 19474 GTTAATACTTTTTCCAGCCT   9 1673 1102131 N/A N/A 19457 19476 ATGTTAATACTTTTTCCAGC  10 1674 1102132 N/A N/A 19458 19477 AATGTTAATACTTTTTCCAG  63 1675 1102133 N/A N/A 19460 19479 ACAATGTTAATACTTTTTCC 108 1676 1102134 N/A N/A 19468 19487 GGATTTTGACAATGTTAATA  20 1677 1102135 N/A N/A 19498 19517 CGATCAATATCATGACCAAC  46 1678 1102136 N/A N/A 19517 19536 AAAAAGTTTCTAAAGTTAAC 187 1679 1102137 N/A N/A 19527 19546 CACAAGATACAAAAAGTTTC 107 1680 1102138 N/A N/A 19530 19549 ACCCACAAGATACAAAAAGT  87 1681 1102139 N/A N/A 19531 19550 AACCCACAAGATACAAAAAG 101 1682 1102140 N/A N/A 19532 19551 TAACCCACAAGATACAAAAA  88 1683 1102141 N/A N/A 19537 19556 TAATTTAACCCACAAGATAC  65 1684 1102142 N/A N/A 19538 19557 CTAATTTAACCCACAAGATA  75 1685 1102143 N/A N/A 19542 19561 AATCCTAATTTAACCCACAA  58 1686 1102144 N/A N/A 19544 19563 GTAATCCTAATTTAACCCAC  39 1687 1102145 N/A N/A 19548 19567 CATAGTAATCCTAATTTAAC  94 1688 1102146 N/A N/A 19564 19583 TCATTTATCACTACCACATA  64 1689 1102147 N/A N/A 19567 19586 ACATCATTTATCACTACCAC  27 1690 1102148 N/A N/A 19571 19590 ATTAACATCATTTATCACTA  80 1691 1102149 N/A N/A 19574 19593 CTAATTAACATCATTTATCA 109 1692 1102150 N/A N/A 19575 19594 CCTAATTAACATCATTTATC  88 1693 1102151 N/A N/A 19576 19595 CCCTAATTAACATCATTTAT  91 1694 1102152 N/A N/A 19577 19596 GCCCTAATTAACATCATTTA  88 1695 1102153 N/A N/A 19579 19598 CGGCCCTAATTAACATCATT 118 1696 1102154 N/A N/A 19580 19599 TCGGCCCTAATTAACATCAT  76 1697 1102155 N/A N/A 19581 19600 CTCGGCCCTAATTAACATCA  88 1698 1102156 N/A N/A 19585 19604 TGCACTCGGCCCTAATTAAC  55 1699 1102157 N/A N/A 19685 19704 GGTCTTACACTATGTTGTAC  73 1700 1102159 N/A N/A 19881 19900 CACATATAACATATAAACAC  99 1701 1102161 N/A N/A 19883 19902 ATCACATATAACATATAAAC 108 1702 1102162 N/A N/A 19887 19906 CACTATCACATATAACATAT  45 1703 1102163 N/A N/A 19918 19937 GTCTCTATAATTTAAAAATG  95 1704 1102164 N/A N/A 20063 20082 CAGCTCAGTTTTTAAAAATC  55 1705 1102165 N/A N/A 20074 20093 TTTATAATTACCAGCTCAGT  36 1706 1102166 N/A N/A 20077 20096 GAATTTATAATTACCAGCTC  23 1707 1102167 N/A N/A 20084 20103 AGGAAGAGAATTTATAATTA  98 1708 1102168 N/A N/A 20105 20124 TGTGAGAAAGTCAGAAGTTC  61 1709 1102169 N/A N/A 20122 20141 TGTCAAAAGATTCCAATTGT 118 1710 1102170 N/A N/A 20124 20143 TTTGTCAAAAGATTCCAATT  77 1711 1102171 N/A N/A 20128 20147 AATTTTTGTCAAAAGATTCC  68 1712 1102172 N/A N/A 20147 20166 AAGTTTTCCCATTACTGATA  49 1713 1102173 N/A N/A 20163 20182 AAATGACAACTACACAAAGT  96 1714 1102174 N/A N/A 20204 20223 CAACATAACTCCAATCATAT  97 1715 1102175 N/A N/A 20222 20241 TTTTTCAAAATATCAGTCCA  45 1716 1102176 N/A N/A 20223 20242 TTTTTTCAAAATATCAGTCC  55 1717 1102177 N/A N/A 20238 20257 AGCTATAATTAAATCTTTTT  67 1718 1102178 N/A N/A 20253 20272 AATGTCTTTATTAATAGCTA  47 1719 1102179 N/A N/A 20254 20273 AAATGTCTTTATTAATAGCT  70 1720 1102180 N/A N/A 20264 20283 TCAGTAGTTTAAATGTCTTT  18 1721 1102181 N/A N/A 20289 20308 CTCCCAAAAGAATAAAAATG  97 1722 1102182 N/A N/A 20294 20313 AAACCCTCCCAAAAGAATAA  92 1723 1102183 N/A N/A 20299 20318 ACATTAAACCCTCCCAAAAG  83 1724 1102184 N/A N/A 20300 20319 AACATTAAACCCTCCCAAAA  90 1725 1102185 N/A N/A 20304 20323 TATAAACATTAAACCCTCCC 102 1726 1102186 N/A N/A 20306 20325 ACTATAAACATTAAACCCTC 117 1727 1102187 N/A N/A 20307 20326 AACTATAAACATTAAACCCT  86 1728 1102188 N/A N/A 20311 20330 TTTAAACTATAAACATTAAA  87 1729 1102189 N/A N/A 20314 20333 TGCTTTAAACTATAAACATT  72 1730 1102190 N/A N/A 20315 20334 TTGCTTTAAACTATAAACAT  84 1731 1102191 N/A N/A 20316 20335 TTTGCTTTAAACTATAAACA  91 1732 1102192 N/A N/A 20318 20337 AGTTTGCTTTAAACTATAAA  75 1733 1102193 N/A N/A 20976 20995 TATCACTATTAAATACTTTT  70 1734 1102195 N/A N/A 20988 21007 ATACTGCAGATTTATCACTA  26 1735 1102197 N/A N/A 21022 21041 GACTGAATAATATGATCTTA  27 1736 1102198 N/A N/A 21051 21070 GAAATATTTCAAGTTGAGCT  15 1737 1102199 N/A N/A 21053 21072 TGGAAATATTTCAAGTTGAG  27 1738 1102200 N/A N/A 21054 21073 CTGGAAATATTTCAAGTTGA  15 1739 1102201 N/A N/A 21055 21074 TCTGGAAATATTTCAAGTTG  43 1740 1102202 N/A N/A 21069 21088 AAGATTGTTTAAACTCTGGA  16 1741 1102203 N/A N/A 21093 21112 AGATACAACCCATCAAAGCT  89 1742 1102204 N/A N/A 21094 21113 TAGATACAACCCATCAAAGC 145 1743 1102205 N/A N/A 21101 21120 TTAAGAATAGATACAACCCA  99 1744 1102206 N/A N/A 21106 21125 ACATGTTAAGAATAGATACA  86 1745 1102207 N/A N/A 21116 21135 AGGAAGTTTCACATGTTAAG  71 1746 1102208 N/A N/A 21152 21171 TGTCAATATTTAAGTTAGTG  93 1747 1102209 N/A N/A 21153 21172 TTGTCAATATTTAAGTTAGT  77 1748 1102210 N/A N/A 21154 21173 ATTGTCAATATTTAAGTTAG  84 1749 1102211 N/A N/A 21178 21197 TTCAAGTTAAACCACTGGAA  77 1750 1102212 N/A N/A 21180 21199 AATTCAAGTTAAACCACTGG  67 1751 1102213 N/A N/A 21260 21279 TTACTTACCTTCCTGTTGTA  73 1752 1102214 N/A N/A 21284 21303 GTAACATTACAAAATGTTCA  78 1753 1102215 N/A N/A 21304 21323 TTATTTAACTACTTCGAAAG  84 1754 1102216 N/A N/A 21311 21330 TGCCTGGTTATTTAACTACT  27 1755 1102217 N/A N/A 21398 21417 CAAATCACAGCCTATCACCA  93 1756 1102218 N/A N/A 21402 21421 CACCCAAATCACAGCCTATC  82 1757 1102219 N/A N/A 21403 21422 TCACCCAAATCACAGCCTAT  62 1758 1102220 N/A N/A 21404 21423 GTCACCCAAATCACAGCCTA  46 1759 1102221 N/A N/A 21495 21514 AGAAAAAGCCATTACTTAGA  51 1760 1102222 N/A N/A 21497 21516 AAAGAAAAAGCCATTACTTA  89 1761 1102223 N/A N/A 21604 21623 CATGTATTTCAAAGAAACTG  62 1762 1102224 N/A N/A 21955 21974 CAAGGGATAGTTTAATCTAG  70 1763 1102225 N/A N/A 22004 22023 GATCCTAAAATCACTGATGA  85 1764 1102226 N/A N/A 22005 22024 AGATCCTAAAATCACTGATG  64 1765 1102227 N/A N/A 22007 22026 TCAGATCCTAAAATCACTGA  83 1766 1102228 N/A N/A 22008 22027 GTCAGATCCTAAAATCACTG  47 1767 1102229 N/A N/A 22009 22028 AGTCAGATCCTAAAATCACT  64 1768 1102231 N/A N/A 22067 22086 GACGATACAGAAATAATTAA  73 1769 1102233 N/A N/A 22204 22223 AACATGGTTTAAAGATAGGA  85 1770 1102234 N/A N/A 22213 22232 AACAGACAAAACATGGTTTA  75 1771 1102235 N/A N/A 22240 22259 GGGTTTAAAGAATGGCTGGA  64 1772 1102236 N/A N/A 22244 22263 AGTAGGGTTTAAAGAATGGC  65 1773 1102237 N/A N/A 22330 22349 CAATGGAGTGATTATGATGA  63 1774 1102238 N/A N/A 22381 22400 TTTGTCATTCAAGTATGATG  41 1775 1102239 N/A N/A 22403 22422 TGGTTTAACCAGGGTTGAGA  18 1776 1102240 N/A N/A 22462 22481 TATGTTATTTTTTAGCCACG  61 1777 1102241 N/A N/A 22464 22483 TTTATGTTATTTTTTAGCCA  89 1778 1102242 N/A N/A 22480 22499 AAACCAATCATCATGTTTTA  55 1779 1102243 N/A N/A 22481 22500 AAAACCAATCATCATGTTTT  56 1780 1102244 N/A N/A 22482 22501 TAAAACCAATCATCATGTTT  47 1781 1102245 N/A N/A 22486 22505 AAAGTAAAACCAATCATCAT  84 1782 1102246 N/A N/A 22505 22524 GGATAGATCATTTAAGAAAA  38 1783 1102247 N/A N/A 22589 22608 ATGAGCTGTGATTATGCTGC  82 1784 1102248 N/A N/A 22691 22710 AAAGTAAAACCTTAGCTAGG  74 1785 1102249 N/A N/A 22692 22711 TAAAGTAAAACCTTAGCTAG 105 1786 1102250 N/A N/A 22695 22714 ATTTAAAGTAAAACCTTAGC 110 1787 1102251 N/A N/A 22701 22720 TAATAAATTTAAAGTAAAAC 111 1788 1102252 N/A N/A 22706 22725 GATTATAATAAATTTAAAGT  76 1789 1102253 N/A N/A 22710 22729 TTGTGATTATAATAAATTTA  77 1790 1102254 N/A N/A 22711 22730 TTTGTGATTATAATAAATTT 109 1791 1102255 N/A N/A 22713 22732 ATTTTGTGATTATAATAAAT  97 1792 1102256 N/A N/A 22715 22734 GAATTTTGTGATTATAATAA 112 1793 1102257 N/A N/A 22748 22767 GTAGAAATATCAGACAGCAC  82 1794 1102258 N/A N/A 22752 22771 CATAGTAGAAATATCAGACA 108 1795 1102259 N/A N/A 22754 22773 AACATAGTAGAAATATCAGA  86 1796 1102260 N/A N/A 22762 22781 ACTAAGAAAACATAGTAGAA  81 1797 1102261 N/A N/A 22794 22813 TTTTTTATAAACACCTTGGA  73 1798 1102262 N/A N/A 22860 22879 GTGAAATTAGTCACCTTGGA  18 1799 1102263 N/A N/A 22865 22884 AAGCTGTGAAATTAGTCACC  41 1800 1102264 N/A N/A 22867 22886 ATAAGCTGTGAAATTAGTCA  58 1801 1102265 N/A N/A 22883 22902 TTAAAGGTTTAAAGACATAA 109 1802 1102267 N/A N/A 22965 22984 AACATAATTTTAATTGCTTC  62 1803 1102269 N/A N/A 22967 22986 AGAACATAATTTTAATTGCT  75 1804 1102270 N/A N/A 22997 23016 ATAAGCAAATTGATAAATTT  91 1805 1102271 N/A N/A 23008 23027 CAGGTGAAGATATAAGCAAA  66 1806 1102272 N/A N/A 23010 23029 CACAGGTGAAGATATAAGCA  78 1807 1102273 N/A N/A 23012 23031 AGCACAGGTGAAGATATAAG  68 1808 1102274 N/A N/A 23037 23056 CATTCATCTATTTAAATAGG  64 1809 1102275 N/A N/A 23150 23169 GAACTGATTATATAAGAGAG  74 1810 1102276 N/A N/A 23175 23194 GGAATATTACAAAAAAAGGG 102 1811 1102277 N/A N/A 23289 23308 AGAGACAATCCTAAGGAAAA  93 1812 1102278 N/A N/A 23290 23309 TAGAGACAATCCTAAGGAAA  52 1813 1102279 N/A N/A 23293 23312 CACTAGAGACAATCCTAAGG  69 1814 1102280 N/A N/A 23603 23622 ATGGAGAAACCCCTTCCATC  74 1815 1102281 N/A N/A 23874 23893 ATACCATTACTAAAAGATGG  79 1816 1102282 N/A N/A 23879 23898 TCCAAATACCATTACTAAAA  49 1817 1102283 N/A N/A 23880 23899 CTCCAAATACCATTACTAAA  41 1818 1102284 N/A N/A 23883 23902 GATCTCCAAATACCATTACT  42 1819 1102285 N/A N/A 23900 23919 GCCAGCACTCAAATTGTGAT  53 1820 1102286 N/A N/A 23927 23946 CATAACAAACCCAGCAGCAA  91 1821 1102287 N/A N/A 23933 23952 TAACTACATAACAAACCCAG  85 1822 1102288 N/A N/A 23936 23955 CAATAACTACATAACAAACC  81 1823 1102289 N/A N/A 23937 23956 ACAATAACTACATAACAAAC  96 1824 1102290 N/A N/A 23939 23958 TCACAATAACTACATAACAA  74 1825 1102291 N/A N/A 23940 23959 TTCACAATAACTACATAACA  78 1826 1102292 N/A N/A 23941 23960 ATTCACAATAACTACATAAC  85 1827 1102293 N/A N/A 23945 23964 GTGAATTCACAATAACTACA  61 1828 1102294 N/A N/A 23946 23965 TGTGAATTCACAATAACTAC  88 1829 1102295 N/A N/A 23947 23966 ATGTGAATTCACAATAACTA  89 1830 1102296 N/A N/A 23959 23978 CTATATTCCTAAATGTGAAT  85 1831 1102297 N/A N/A 23964 23983 AAACCCTATATTCCTAAATG 107 1832 1102298 N/A N/A 23970 23989 AATTAAAAACCCTATATTCC  91 1833 1102299 N/A N/A 23971 23990 GAATTAAAAACCCTATATTC  93 1834 1102300 N/A N/A 23984 24003 ATCTAAAATCAAAGAATTAA  93 1835 1102301 N/A N/A 23985 24004 TATCTAAAATCAAAGAATTA 127 1836 1102303 N/A N/A 23987 24006 AGTATCTAAAATCAAAGAAT  93 1837 1102305 N/A N/A 23990 24009 ACAAGTATCTAAAATCAAAG  83 1838 1102306 N/A N/A 23991 24010 TACAAGTATCTAAAATCAAA 124 1839 1102307 N/A N/A 23998 24017 AAAAAGATACAAGTATCTAA 113 1840 1102308 N/A N/A 24001 24020 AGAAAAAAGATACAAGTATC  82 1841 1102309 N/A N/A 24017 24036 AGGTTTTAAATATAAAAGAA  94 1842 1102310 N/A N/A 24020 24039 CCAAGGTTTTAAATATAAAA  75 1843 1102311 N/A N/A 24070 24089 GCTGAAGGCCAAAGGTAGAC  72 1844 1102312 N/A N/A 24092 24111 TAGGAAAACCACAGCATGGT  85 1845 1102313 N/A N/A 24093 24112 TTAGGAAAACCACAGCATGG  80 1846 1102314 N/A N/A 24094 24113 GTTAGGAAAACCACAGCATG  94 1847 1102315 N/A N/A 24145 24164 ACAGATGATATTTAAGATCC  66 1848 1102316 N/A N/A 24158 24177 ATAGATCTTATTTACAGATG 103 1849 1102317 N/A N/A 24194 24213 CAAGACTAAAGATAAAAGTT  85 1850 1102318 N/A N/A 24197 24216 TGTCAAGACTAAAGATAAAA  82 1851 1102319 N/A N/A 24199 24218 GATGTCAAGACTAAAGATAA  76 1852 1102320 N/A N/A 24229 24248 GGAGTTAGTCAAAGCTAGGT  47 1853 1102321 N/A N/A 24231 24250 TAGGAGTTAGTCAAAGCTAG  62 1854 1102322 N/A N/A 24246 24265 TGGAGATGCCAAAGCTAGGA  28 1855 1102323 N/A N/A 24292 24311 TCTTTCATAGACATGTTCAG  64 1856 1102324 N/A N/A 24297 24316 ATAAGTCTTTCATAGACATG  98 1857 1102325 N/A N/A 24337 24356 AATGGAAAACCTGATGGATA  84 1858 1102326 N/A N/A 24355 24374 AAGAGTCACCCTTATGGAAA  68 1859 1102327 N/A N/A 24382 24401 CGGTATAATATATAGGAACC  48 1860 1102328 N/A N/A 24384 24403 GTCGGTATAATATATAGGAA  23 1861 1102329 N/A N/A 24819 24838 GGTTTTATTCAAGACTTCAC   9 1862 1102330 N/A N/A 24823 24842 CTTGGGTTTTATTCAAGACT  54 1863 1102331 N/A N/A 24892 24911 ACCATGGTATTCTATGAAGA  70 1864 1102332 N/A N/A 24909 24928 AATAAATATGCCAGCTCACC  39 1865 1102333 N/A N/A 24914 24933 TGTATAATAAATATGCCAGC  23 1866 1102334 N/A N/A 24915 24934 TTGTATAATAAATATGCCAG  31 1867 1102335 N/A N/A 24936 24955 GCCAGTAAAATTGTTTCTGT  41 1868 1102336 N/A N/A 24994 25013 TGAACATTTTTTATGAGGAC   8 1869 1102337 N/A N/A 24995 25014 TTGAACATTTTTTATGAGGA  26 1870 1102339 N/A N/A 25019 25038 AATGGAAAACCTCAAAATAG  75 1871 1102341 N/A N/A 25438 25457 ATCTAACTGATTTAAGTTTC 112 1872 1102342 N/A N/A 25449 25468 TACCTAAAACAATCTAACTG 103 1873 1102343 N/A N/A 25453 25472 GCTATACCTAAAACAATCTA  68 1874 1102344 N/A N/A 25454 25473 GGCTATACCTAAAACAATCT  55 1875 1102345 N/A N/A 25455 25474 GGGCTATACCTAAAACAATC  55 1876 1102346 N/A N/A 25457 25476 ATGGGCTATACCTAAAACAA 101 1877 1102347 N/A N/A 25473 25492 CACACAAAAACCAAGGATGG  59 1878 1102348 N/A N/A 25499 25518 CCAGGGTTTCCCCAAGCTAG  54 1879 1102349 N/A N/A 25507 25526 CCAGAAATCCAGGGTTTCCC  73 1880 1102350 N/A N/A 25509 25528 TTCCAGAAATCCAGGGTTTC  56 1881 1102351 N/A N/A 25513 25532 ATGATTCCAGAAATCCAGGG  18 1882 1102352 N/A N/A 25515 25534 ATATGATTCCAGAAATCCAG  41 1883 1102353 N/A N/A 25521 25540 GTCTAAATATGATTCCAGAA   6 1884 1102354 N/A N/A 25545 25564 ATTACATTAGTCTAGTGTGA  51 1885 1102355 N/A N/A 25550 25569 AAAGAATTACATTAGTCTAG  64 1886 1102356 N/A N/A 25551 25570 AAAAGAATTACATTAGTCTA  87 1887 1102357 N/A N/A 25554 25573 CCCAAAAGAATTACATTAGT  60 1888 1102358 N/A N/A 25555 25574 TCCCAAAAGAATTACATTAG  67 1889 1102359 N/A N/A 25556 25575 ATCCCAAAAGAATTACATTA  95 1890 1102360 N/A N/A 25561 25580 TTTGCATCCCAAAAGAATTA  75 1891 1102361 N/A N/A 25590 25609 AAAAGCTATTTAAGGTGTCA  26 1892 1102362 N/A N/A 25591 25610 TAAAAGCTATTTAAGGTGTC  56 1893 1102363 N/A N/A 25592 25611 CTAAAAGCTATTTAAGGTGT  67 1894 1102364 N/A N/A 25600 25619 CCAAATACCTAAAAGCTATT  84 1895 1102365 N/A N/A 25601 25620 GCCAAATACCTAAAAGCTAT 108 1896 1102366 N/A N/A 25602 25621 AGCCAAATACCTAAAAGCTA  86 1897 1102367 N/A N/A 25603 25622 AAGCCAAATACCTAAAAGCT  71 1898 1102368 N/A N/A 25604 25623 GAAGCCAAATACCTAAAAGC  54 1899 1102369 N/A N/A 25605 25624 GGAAGCCAAATACCTAAAAG  44 1900 1102370 N/A N/A 25632 25651 ACCCCTTGTAACTAAAAATA  93 1901 1102371 N/A N/A 25689 25708 TGGCTAAAACTAATCATCTG  71 1902 1102372 N/A N/A 25690 25709 ATGGCTAAAACTAATCATCT  70 1903 1102373 N/A N/A 25691 25710 CATGGCTAAAACTAATCATC  98 1904 1102375 N/A N/A 25805 25824 CATTACCCTTCATATATACA  73 1905 1102377 N/A N/A 25814 25833 TCCTTAATACATTACCCTTC  62 1906 1102378 N/A N/A 25822 25841 GTCGATACTCCTTAATACAT  23 1907 1102379 N/A N/A 26243 26262 CTACAAATTATTGTTTCTGG  17 1908 1102380 N/A N/A 26245 26264 GGCTACAAATTATTGTTTCT  25 1909 1102381 N/A N/A 26246 26265 AGGCTACAAATTATTGTTTC  58 1910 1102382 N/A N/A 26247 26266 AAGGCTACAAATTATTGTTT  50 1911 1102383 N/A N/A 26249 26268 TGAAGGCTACAAATTATTGT  40 1912 1102384 N/A N/A 26311 26330 ACTGTTAAACATATGATACT  73 1913 1102385 N/A N/A 26322 26341 TCTTGGTTTCTACTGTTAAA  78 1914 1102386 N/A N/A 26455 26474 AAAGGGCCCTACTAATATAG 107 1915 1102387 N/A N/A 26475 26494 TGAGAAATAAATATGTCTGT  79 1916 1102388 N/A N/A 26525 26544 CCTCACTTTCTCCATTGTAA  47 1917 1102389 N/A N/A 26577 26596 TCTTATACTTACTAGTAAAG  77 1918 1102390 N/A N/A 26580 26599 GATTCTTATACTTACTAGTA  70 1919 1102391 N/A N/A 26581 26600 TGATTCTTATACTTACTAGT  92 1920 1102392 N/A N/A 26584 26603 TAATGATTCTTATACTTACT  59 1921 1102393 N/A N/A 26585 26604 ATAATGATTCTTATACTTAC  87 1922 1102394 N/A N/A 26593 26612 TAGTCCAAATAATGATTCTT  50 1923 1102395 N/A N/A 26629 26648 TGGAAAAAAATACAAGCTGA  88 1924 1102396 N/A N/A 26630 26649 CTGGAAAAAAATACAAGCTG  68 1925 1102397 N/A N/A 26631 26650 ACTGGAAAAAAATACAAGCT  84 1926 1102398 N/A N/A 26632 26651 CACTGGAAAAAAATACAAGC  99 1927 1102399 N/A N/A 26680 26699 GATTCAAAATTGATGTAAAA  95 1928 1102400 N/A N/A 26681 26700 AGATTCAAAATTGATGTAAA  91 1929 1102401 N/A N/A 26684 26703 AAGAGATTCAAAATTGATGT 124 1930 1102402 N/A N/A 26685 26704 AAAGAGATTCAAAATTGATG  86 1931 1102403 N/A N/A 26707 26726 AAAATCAACCTAACCAGTTA  87 1932 1102404 N/A N/A 26708 26727 AAAAATCAACCTAACCAGTT 109 1933 1102405 N/A N/A 26714 26733 AAAGGCAAAAATCAACCTAA 102 1934 1102406 N/A N/A 26733 26752 ATAGAATAACCTAAAAAAAA  78 1935 1102407 N/A N/A 26734 26753 TATAGAATAACCTAAAAAAA 131 1936 1102408 N/A N/A 26737 26756 AAATATAGAATAACCTAAAA 102 1937 1102409 N/A N/A 26739 26758 ACAAATATAGAATAACCTAA  95 1938 1102411 N/A N/A 26870 26889 GGCCTCATTTTTACCTTTGC  85 1939 1102413 N/A N/A 26898 26917 GAAATACTACCATATATTCC  89 1940 1102414 N/A N/A 26923 26942 AGCATGAAAATTTAATTCTC  91 1941 1102415 N/A N/A 26986 27005 TTCACTAAAATATAAGGTCC  73 1942 1102416 N/A N/A 26995 27014 CTAATAAACTTCACTAAAAT 111 1943 1102417 N/A N/A 26996 27015 ACTAATAAACTTCACTAAAA  70 1944 1102418 N/A N/A 27008 27027 ATTCAAGTTTAAACTAATAA  85 1945 1102419 N/A N/A 27027 27046 TAAGTATTTCAAAGAGTTGA  37 1946 1102420 N/A N/A 27029 27048 TTTAAGTATTTCAAAGAGTT 110 1947 1102421 N/A N/A 27036 27055 TAATATATTTAAGTATTTCA  82 1948 1102422 N/A N/A 27043 27062 ACTAAGTTAATATATTTAAG 119 1949 1102423 N/A N/A 27064 27083 AGGAATATACCATACCAGCT  34 1950 1102424 N/A N/A 27066 27085 CTAGGAATATACCATACCAG  19 1951 1102425 N/A N/A 27391 27410 CTAGTAATATAATGATTGTG  37 1952 1102426 N/A N/A 27394 27413 GCTCTAGTAATATAATGATT  35 1953 1102427 N/A N/A 27407 27426 TTCTGGCAAATAAGCTCTAG  44 1954 1102428 N/A N/A 27470 27489 TTAGACATAACATAAAGGCA  68 1955 1102429 N/A N/A 27481 27500 AATCTTCTATTTTAGACATA  93 1956 1102430 N/A N/A 27486 27505 CAACCAATCTTCTATTTTAG  84 1957 1102431 N/A N/A 27487 27506 GCAACCAATCTTCTATTTTA  83 1958 1102432 N/A N/A 27492 27511 TAACTGCAACCAATCTTCTA 114 1959 1102433 N/A N/A 27518 27537 ACTCTAAAGAACAAAAGCAC  85 1960 1102434 N/A N/A 27523 27542 TATGGACTCTAAAGAACAAA  75 1961 1102435 N/A N/A 27690 27709 GTCTTTACCTTGCATACTTA  65 1962 1102436 N/A N/A 27697 27716 TCAGAATGTCTTTACCTTGC 104 1963 1102437 N/A N/A 27712 27731 TGAATACAACACACATCAGA  81 1964 1102438 N/A N/A 27718 27737 CAGCAATGAATACAACACAC  84 1965 1102439 N/A N/A 27720 27739 TTCAGCAATGAATACAACAC  75 1966 1102440 N/A N/A 27729 27748 AATCAATTCTTCAGCAATGA 100 1967 1102441 N/A N/A 27730 27749 GAATCAATTCTTCAGCAATG  70 1968 1102442 N/A N/A 27748 27767 GAAATCTAAGAATAATTGGA 108 1969 1102443 N/A N/A 27763 27782 TACATTAACTTCCATGAAAT  91 1970 1102444 N/A N/A 27770 27789 CTAAGAGTACATTAACTTCC  68 1971 1102445 N/A N/A 27786 27805 AATTGTCAAAACACCTCTAA  77 1972 1102447 N/A N/A 27824 27843 AAAGGGAAAGCCCACTATAT 118 1973 1102449 N/A N/A 27848 27867 AGTGATTTCCATTATAAGAA  71 1974 1102450 N/A N/A 27849 27868 AAGTGATTTCCATTATAAGA  69 1975 1102451 N/A N/A 27872 27891 CCTAATAAAATATAGGTTGT  82 1976 1102452 N/A N/A 27873 27892 TCCTAATAAAATATAGGTTG 108 1977 1102453 N/A N/A 27874 27893 CTCCTAATAAAATATAGGTT  86 1978 1102454 N/A N/A 27875 27894 ACTCCTAATAAAATATAGGT 166 1979 1102455 N/A N/A 27882 27901 TATAACTACTCCTAATAAAA  82 1980 1102456 N/A N/A 27885 27904 AAATATAACTACTCCTAATA 109 1981 1102457 N/A N/A 27887 27906 AAAAATATAACTACTCCTAA 120 1982 1102458 N/A N/A 27893 27912 AGGAGTAAAAATATAACTAC 117 1983 1102459 N/A N/A 27894 27913 CAGGAGTAAAAATATAACTA 109 1984 1102460 N/A N/A 27895 27914 CCAGGAGTAAAAATATAACT  91 1985 1102461 N/A N/A 27903 27922 TAAAATAACCAGGAGTAAAA  88 1986 1102462 N/A N/A 27908 27927 CCAAATAAAATAACCAGGAG  86 1987 1102463 N/A N/A 27910 27929 AACCAAATAAAATAACCAGG  89 1988 1102464 N/A N/A 27916 27935 TGTTGAAACCAAATAAAATA 108 1989 1102465 N/A N/A 27943 27962 CCACAATTTACTATTGTGTT  96 1990 1102466 N/A N/A 27947 27966 AAAACCACAATTTACTATTG  94 1991 1102467 N/A N/A 27953 27972 AAGATTAAAACCACAATTTA  89 1992 1102468 N/A N/A 27966 27985 ACTGATACCCACAAAGATTA  77 1993 1102469 N/A N/A 27974 27993 AAGGGTCAACTGATACCCAC  89 1994 1102470 N/A N/A 28007 28026 ATGGCACATATTTATGTAAC  51 1995 1102471 N/A N/A 28083 28102 AGTTGCATAGCCAATAAATG  54 1996 1102472 N/A N/A 28126 28145 TATCACTAAAAAACTGGGCC 100 1997 1102473 N/A N/A 28127 28146 ATATCACTAAAAAACTGGGC  79 1998 1102474 N/A N/A 28128 28147 TATATCACTAAAAAACTGGG  94 1999 1102475 N/A N/A 28129 28148 TTATATCACTAAAAAACTGG 102 2000 1102476 N/A N/A 28131 28150 GTTTATATCACTAAAAAACT  90 2001 1102477 N/A N/A 28132 28151 AGTTTATATCACTAAAAAAC 146 2002 1102478 N/A N/A 28133 28152 TAGTTTATATCACTAAAAAA  87 2003 1102479 N/A N/A 28134 28153 ATAGTTTATATCACTAAAAA 101 2004 1102480 N/A N/A 28136 28155 TGATAGTTTATATCACTAAA  99 2005 1102481 N/A N/A 28138 28157 ATTGATAGTTTATATCACTA  94 2006 1102483 N/A N/A 28195 28214 TGTCTTAACATTTTTCTTTG  47 2007 1102485 N/A N/A 28229 28248 CACTTCAAACTTTTAATTAA  94 2008 1102486 N/A N/A 28230 28249 CCACTTCAAACTTTTAATTA  80 2009 1102487 N/A N/A 28233 28252 AACCCACTTCAAACTTTTAA  75 2010 1102488 N/A N/A 28235 28254 AAAACCCACTTCAAACTTTT  83 2011 1102489 N/A N/A 28271 28290 AAGCAAATACATATGAGTTA  59 2012 1102490 N/A N/A 28273 28292 AGAAGCAAATACATATGAGT  24 2013 1102491 N/A N/A 28274 28293 TAGAAGCAAATACATATGAG  83 2014 1102492 N/A N/A 28288 28307 ATTTCATTAGAAAGTAGAAG  98 2015 1102493 N/A N/A 28293 28312 AAATAATTTCATTAGAAAGT  97 2016 1102494 N/A N/A 28297 28316 TGATAAATAATTTCATTAGA  95 2017 1102495 N/A N/A 28340 28359 TTAATGAAATTTCAATTTTA 110 2018 1102496 N/A N/A 28351 28370 TAATCTTCCCATTAATGAAA  85 2019 1102497 N/A N/A 28355 28374 AAAATAATCTTCCCATTAAT  83 2020 1102498 N/A N/A 28360 28379 GGATAAAAATAATCTTCCCA  79 2021 1102499 N/A N/A 28361 28380 AGGATAAAAATAATCTTCCC  62 2022 1102500 N/A N/A 28378 28397 AGAGGCAAGAAAAGTTCAGG  54 2023 1102501 N/A N/A 28414 28433 GATTGCACACCATATGGAGT  63 2024 1102502 N/A N/A 28431 28450 CTATTAATCAAAAATGGGAT 119 2025 1102503 N/A N/A 28432 28451 TCTATTAATCAAAAATGGGA  79 2026 1102504 N/A N/A 28434 28453 ACTCTATTAATCAAAAATGG  80 2027 1102505 N/A N/A 28437 28456 AGGACTCTATTAATCAAAAA  77 2028 1102506 N/A N/A 28439 28458 GCAGGACTCTATTAATCAAA 105 2029 1102507 N/A N/A 28452 28471 CCCTGCTAATCCAGCAGGAC 130 2030 1102508 N/A N/A 28477 28496 AAAGAAATCTAAAGCTGATT 115 2031 1102509 N/A N/A 28810 28829 AGAATATTCTACTCTTCTGG 111 2032 1102510 N/A N/A 28813 28832 TTAAGAATATTCTACTCTTC 103 2033 1102511 N/A N/A 28817 28836 CTCTTTAAGAATATTCTACT  65 2034 1102512 N/A N/A 28818 28837 TCTCTTTAAGAATATTCTAC  80 2035 1102513 N/A N/A 28872 28891 TTCAAGCAACAATATGTTTG  86 2036 1102514 N/A N/A 28880 28899 TTTACCAATTCAAGCAACAA 109 2037 1102515 N/A N/A 28881 28900 ATTTACCAATTCAAGCAACA 128 2038 1102516 N/A N/A 28883 28902 GTATTTACCAATTCAAGCAA  67 2039 1102517 N/A N/A 28886 28905 ACTGTATTTACCAATTCAAG  86 2040 1102519 N/A N/A 28895 28914 AAACCAATCACTGTATTTAC 126 2041 1102521 N/A N/A 28902 28921 ACAACAAAAACCAATCACTG 100 2042 1102522 N/A N/A 28903 28922 CACAACAAAAACCAATCACT  78 2043 1102523 N/A N/A 28922 28941 ACCTGAAAACAAAACACAAC  95 2044 1102524 N/A N/A 28923 28942 TACCTGAAAACAAAACACAA  25 2045 1102525 N/A N/A 28926 28945 AACTACCTGAAAACAAAACA  78 2046 1102526 N/A N/A 29022 29041 TTTACTTTTCAAAGTAGGCT  82 2047 1102527 N/A N/A 29023 29042 CTTTACTTTTCAAAGTAGGC 109 2048 1102528 N/A N/A 29025 29044 TACTTTACTTTTCAAAGTAG 109 2049 1102529 N/A N/A 29028 29047 AACTACTTTACTTTTCAAAG  99 2050 1102530 N/A N/A 29032 29051 TACCAACTACTTTACTTTTC  85 2051 1102531 N/A N/A 29035 29054 TTGTACCAACTACTTTACTT  88 2052 1102532 N/A N/A 29051 29070 AACATGCTACTTTAACTTGT  78 2053 1102533 N/A N/A 29062 29081 AGCAAATATTAAACATGCTA 109 2054 1102534 N/A N/A 29074 29093 CAAAATAGCCAAAGCAAATA  82 2055 1102535 N/A N/A 29076 29095 GACAAAATAGCCAAAGCAAA  62 2056 1102536 N/A N/A 29085 29104 TTACAAATAGACAAAATAGC  76 2057 1102537 N/A N/A 29091 29110 AACCATTTACAAATAGACAA  63 2058 1102538 N/A N/A 29096 29115 GCAGTAACCATTTACAAATA  42 2059 1102539 N/A N/A 29119 29138 ATTCAAATATTCACAGGATT  55 2060 1102540 N/A N/A 29125 29144 AAATACATTCAAATATTCAC  89 2061 1102541 N/A N/A 29476 29495 GCCGTAAATTTTTATTTTTA  16 2062 1102542 N/A N/A 29477 29496 TGCCGTAAATTTTTATTTTT  40 2063 1102543 N/A N/A 29529 29548 GTTTAAAAAATTTATCCAGT  82 2064 1102544 N/A N/A 29530 29549 AGTTTAAAAAATTTATCCAG  88 2065 1102545 N/A N/A 29531 29550 CAGTTTAAAAAATTTATCCA 109 2066 1102546 N/A N/A 29535 29554 CACTCAGTTTAAAAAATTTA  78 2067 1102547 N/A N/A 29548 29567 ATAAGGTTTCCTTCACTCAG  22 2068 1102548 N/A N/A 29561 29580 TAAATGAAATTTTATAAGGT 109 2069 1102549 N/A N/A 29585 29604 GTCCTAATTTCATTTTTCTT  30 2070 1102550 N/A N/A 29587 29606 TTGTCCTAATTTCATTTTTC  58 2071 1102551 N/A N/A 29645 29664 AGGGTTAATCAGGTAAGCAA   8 2072 1102552 N/A N/A 29647 29666 GCAGGGTTAATCAGGTAAGC  17 2073 1102553 N/A N/A 29807 29826 TTGATCCAGATTTATGGTTT  28 2074 1102555 N/A N/A 29812 29831 AGGAGTTGATCCAGATTTAT  28 2075 1102557 N/A N/A 29881 29900 AATGTATTTTCATATGGTGG  10 2076 1102558 N/A N/A 29901 29920 AATGATAGTTACTTGAAAAG  87 2077 1102559 N/A N/A 30269 30288 TCTTGTAATCTTTAACATGA  84 2078 1102560 N/A N/A 30280 30299 CTGATTATTTATCTTGTAAT  34 2079 1102561 N/A N/A 30281 30300 TCTGATTATTTATCTTGTAA  34 2080 1102562 N/A N/A 30282 30301 GTCTGATTATTTATCTTGTA  14 2081 1102563 N/A N/A 30283 30302 GGTCTGATTATTTATCTTGT  15 2082 1102564 N/A N/A 30350 30369 TGGATGAAATACAGCAAATA  42 2083 1102565 N/A N/A 30354 30373 AGAATGGATGAAATACAGCA  82 2084 1102566 N/A N/A 30376 30395 AATGTGAAACTATGTGCATC  57 2085 1102567 N/A N/A 30378 30397 GAAATGTGAAACTATGTGCA  29 2086 1102568 N/A N/A 30380 30399 TTGAAATGTGAAACTATGTG  58 2087 1102569 N/A N/A 30398 30417 TTCTCAATTTCAGAGACATT  46 2088 1102570 N/A N/A 30399 30418 CTTCTCAATTTCAGAGACAT  38 2089 1102571 N/A N/A 30400 30419 GCTTCTCAATTTCAGAGACA  37 2090 1102572 N/A N/A 30436 30455 GTGCTGCTAATATACTGTCA  26 2091 1102573 N/A N/A 30452 30471 GAGCCAATATTTATAGGTGC  21 2092 1102574 N/A N/A 30453 30472 TGAGCCAATATTTATAGGTG   7 2093 1102575 N/A N/A 30473 30492 TTATACCATCAAATGTAAAA  83 2094 1102576 N/A N/A 30475 30494 CATTATACCATCAAATGTAA  59 2095 1102577 N/A N/A 30477 30496 TTCATTATACCATCAAATGT  53 2096 1102578 N/A N/A 30478 30497 CTTCATTATACCATCAAATG  30 2097 1102579 N/A N/A 30479 30498 TCTTCATTATACCATCAAAT   9 2098 1102580 N/A N/A 30490 30509 GGTAAATATTTTCTTCATTA   9 2099 1102581 N/A N/A 30495 30514 AAAAAGGTAAATATTTTCTT  84 2100 1102582 N/A N/A 30520 30539 GTTGTGACTTAAAAACAAAA  74 2101 1102583 N/A N/A 30523 30542 TGAGTTGTGACTTAAAAACA  49 2102 1102584 N/A N/A 30546 30565 CAGAATTTTCCTTCATCTAC  89 2103 1102585 N/A N/A 30547 30566 TCAGAATTTTCCTTCATCTA  42 2104 1102586 N/A N/A 30548 30567 ATCAGAATTTTCCTTCATCT  34 2105 1102587 N/A N/A 30574 30593 ATCTCACATTAAGAGGATGT  69 2106 1102588 N/A N/A 30576 30595 ATATCTCACATTAAGAGGAT  69 2107 1102589 N/A N/A 30577 30596 AATATCTCACATTAAGAGGA  41 2108 1102591 N/A N/A 30582 30601 CTAGAAATATCTCACATTAA  88 2109 1102593 N/A N/A 30587 30606 AAAGACTAGAAATATCTCAC  46 2110 1102594 N/A N/A 30588 30607 TAAAGACTAGAAATATCTCA  65 2111 1102595 N/A N/A 30600 30619 ATCTATACTGAATAAAGACT  72 2112 1102596 N/A N/A 30605 30624 CATTAATCTATACTGAATAA  98 2113 1102597 N/A N/A 30606 30625 CCATTAATCTATACTGAATA  64 2114 1102598 N/A N/A 30607 30626 GCCATTAATCTATACTGAAT  19 2115 1102599 N/A N/A 30608 30627 AGCCATTAATCTATACTGAA   7 2116 1102600 N/A N/A 30609 30628 TAGCCATTAATCTATACTGA  25 2117 1102601 N/A N/A 30610 30629 TTAGCCATTAATCTATACTG  80 2118 1102602 N/A N/A 30611 30630 ATTAGCCATTAATCTATACT  65 2119 1102603 N/A N/A 30613 30632 TAATTAGCCATTAATCTATA  66 2120 1102604 N/A N/A 30614 30633 ATAATTAGCCATTAATCTAT  69 2121 1102605 N/A N/A 30616 30635 ATATAATTAGCCATTAATCT  63 2122 1102606 N/A N/A 30625 30644 AAATTTAACATATAATTAGC  89 2123 1102607 N/A N/A 30632 30651 TACTTTGAAATTTAACATAT  92 2124 1102608 N/A N/A 30651 30670 AAAAAGCACTAATAAGCACT  59 2125 1102609 N/A N/A 30659 30678 TTAAAAGTAAAAAGCACTAA  91 2126 1102610 N/A N/A 30675 30694 AAGTTAATTTTGAAACTTAA 118 2127 1102611 N/A N/A 30697 30716 TTTGGAGTTTATTATAATAA  55 2128 1102612 N/A N/A 30723 30742 TGCTAGTTTTTCTACTTTTG  13 2129 1102613 N/A N/A 31103 31122 ATGGGAGTATTATAAAACGA  38 2130 1102614 N/A N/A 31121 31140 CAGTGGAAAGAATGGGAGAT  48 2131 1102615 N/A N/A 31147 31166 AAAATAATCCAAACTTGCAG  36 2132 1102616 N/A N/A 31150 31169 TACAAAATAATCCAAACTTG  84 2133 1102617 N/A N/A 31152 31171 GTTACAAAATAATCCAAACT  71 2134 1102618 N/A N/A 31153 31172 TGTTACAAAATAATCCAAAC  82 2135 1102619 N/A N/A 31154 31173 TTGTTACAAAATAATCCAAA  80 2136 1102620 N/A N/A 31179 31198 TATAGAATAATATGATGATT  81 2137 1102621 N/A N/A 31197 31216 GACACATATTAAAATGGTTA  25 2138 1102622 N/A N/A 31237 31256 GCATTTAACTATGTTAAAAA  77 2139 1102623 N/A N/A 31238 31257 AGCATTTAACTATGTTAAAA  88 2140 1102624 N/A N/A 31240 31259 ATAGCATTTAACTATGTTAA  85 2141 1102625 N/A N/A 31251 31270 ATTTTATGACAATAGCATTT  28 2142 1102627 N/A N/A 31285 31304 TGATATAGAATTACAATTAA 112 2143 1102629 N/A N/A 31647 31666 AAGTAGATTTAAGTTATTTT 118 2144 1102630 N/A N/A 31650 31669 ATTAAGTAGATTTAAGTTAT 136 2145 1102631 N/A N/A 31657 31676 TTTTCTAATTAAGTAGATTT  95 2146 1102632 N/A N/A 31659 31678 GTTTTTCTAATTAAGTAGAT 103 2147 1102633 N/A N/A 31660 31679 AGTTTTTCTAATTAAGTAGA  72 2148 1102634 N/A N/A 31662 31681 TTAGTTTTTCTAATTAAGTA 123 2149 1102635 N/A N/A 31664 31683 TGTTAGTTTTTCTAATTAAG  73 2150 1102636 N/A N/A 32030 32049 TGCTTTAATTTCTATATTTC  71 2151 1102637 N/A N/A 32676 32695 GCCAAAATACTAACATCAGT 110 2152 1102638 N/A N/A 32677 32696 TGCCAAAATACTAACATCAG  42 2153 1102639 N/A N/A 32678 32697 GTGCCAAAATACTAACATCA  26 2154 1102640 N/A N/A 32679 32698 TGTGCCAAAATACTAACATC  52 2155 1102641 N/A N/A 32680 32699 ATGTGCCAAAATACTAACAT  42 2156 1102642 N/A N/A 32682 32701 GAATGTGCCAAAATACTAAC  36 2157 1102643 N/A N/A 32683 32702 AGAATGTGCCAAAATACTAA  47 2158 1102644 N/A N/A 32691 32710 ACAGAAAAAGAATGTGCCAA  48 2159 1102645 N/A N/A 32726 32745 GAGTACAACACTTACAAGGT  24 2160 1102646 N/A N/A 32750 32769 AGACTATTTACTGTCATAGG  15 2161 1102647 N/A N/A 32752 32771 AAAGACTATTTACTGTCATA  54 2162 1102648 N/A N/A 32754 32773 ACAAAGACTATTTACTGTCA  44 2163 1102649 N/A N/A 32762 32781 AGCCTGTTACAAAGACTATT  64 2164 1102650 N/A N/A 32777 32796 TATGAAATATCATGCAGCCT  47 2165 1102651 N/A N/A 32778 32797 TTATGAAATATCATGCAGCC  63 2166 1102652 N/A N/A 32786 32805 CATTCATTTTATGAAATATC  93 2167 1102653 N/A N/A 32807 32826 ACATATAAATTATGCCACAT  49 2168 1102654 N/A N/A 32826 32845 AGCAGAATTCAAAAGGCTCA  65 2169 1102655 N/A N/A 32864 32883 GCAATATAAGAATTGTTCAT  19 2170 1102656 N/A N/A 32933 32952 TCCTTTAACCCAATAATCTG  91 2171 1102657 N/A N/A 32940 32959 GTTCATATCCTTTAACCCAA   8 2172 1102658 N/A N/A 32975 32994 AGCAATTTAGAAATCTGTTC  68 2173 1102659 N/A N/A 32993 33012 ATGGGAATTATTCTGGAAAG  40 2174 1102660 N/A N/A 33005 33024 TGAAAGTATCACATGGGAAT  39 2175 1102661 N/A N/A 33013 33032 AAACATGGTGAAAGTATCAC  33 2176 1102663 N/A N/A 33370 33389 GATGTATGTCTTTAGACCAT  25 2177 1102665 N/A N/A 33447 33466 GCAGTTTATTTTTATGCTTT  40 2178 1102666 N/A N/A 33492 33511 GTTTCATATTTTTAATCCAG   7 2179 1102667 N/A N/A 33497 33516 TGGAAGTTTCATATTTTTAA  14 2180 1102668 N/A N/A 33498 33517 TTGGAAGTTTCATATTTTTA  18 2181 1102669 N/A N/A 33875 33894 ACTTACTTAGTCATTATTGG  27 2182 1102670 N/A N/A 33880 33899 TTATAACTTACTTAGTCATT  55 2183 1102671 N/A N/A 33882 33901 TGTTATAACTTACTTAGTCA  27 2184 1102672 N/A N/A 33884 33903 CTTGTTATAACTTACTTAGT  48 2185 1102673 N/A N/A 33921 33940 TGTTTACTAAAAAGCACTAG  94 2186 1102674 N/A N/A 33922 33941 CTGTTTACTAAAAAGCACTA 102 2187 1102675 N/A N/A 33923 33942 CCTGTTTACTAAAAAGCACT 105 2188 1102676 N/A N/A 33925 33944 ACCCTGTTTACTAAAAAGCA 110 2189 1102677 N/A N/A 33956 33975 GAACATTTTTAAAAGGGTAC  13 2190 1102678 N/A N/A 33957 33976 CGAACATTTTTAAAAGGGTA  15 2191 1102679 N/A N/A 33959 33978 TTCGAACATTTTTAAAAGGG  22 2192 1102680 N/A N/A 33973 33992 GAGGTATATCGATATTCGAA  41 2193 1102681 N/A N/A 33993 34012 ATCCTCCACCAAGTAGGAAG  78 2194 1102682 N/A N/A 34001 34020 CTCAATCAATCCTCCACCAA  97 2195 1102683 N/A N/A 34014 34033 GCACACTTTCCTCCTCAATC  15 2196 1102684 N/A N/A 34030 34049 GCTGGTAACCATCACTGCAC  12 2197 1102685 N/A N/A 34031 34050 AGCTGGTAACCATCACTGCA  79 2198 1102686 N/A N/A 34051 34070 AAGTCAAGCCAAGAGGCTGA  88 2199 1102687 N/A N/A 34053 34072 CAAAGTCAAGCCAAGAGGCT  83 2200 1102688 N/A N/A 34058 34077 ATTTGCAAAGTCAAGCCAAG  55 2201 1102689 N/A N/A 34071 34090 AATTCTCACCAGTATTTGCA  45 2202 1102690 N/A N/A 34082 34101 AGCTCTTTCCAAATTCTCAC  24 2203 1102691 N/A N/A 34095 34114 TAAGATATTCTCAAGCTCTT  40 2204 1102692 N/A N/A 34097 34116 TGTAAGATATTCTCAAGCTC  29 2205 1102693 N/A N/A 34100 34119 CTATGTAAGATATTCTCAAG  58 2206 1102694 N/A N/A 34102 34121 GACTATGTAAGATATTCTCA  31 2207 1102695 N/A N/A 34111 34130 GCAACATGTGACTATGTAAG  16 2208 1102696 N/A N/A 34130 34149 TAGTTCTTAACTCTTCTCAG  34 2209 1102697 N/A N/A 34133 34152 AGTTAGTTCTTAACTCTTCT  39 2210 1102699 N/A N/A 34147 34166 AATGAACATCAAGAAGTTAG  54 2211 1102701 N/A N/A 34228 34247 AATTTTAGTGAAAGGCAAAT  84 2212 1102702 N/A N/A 34235 34254 AATCAGGAATTTTAGTGAAA  53 2213 1102703 N/A N/A 34241 34260 CTAAGTAATCAGGAATTTTA 106 2214 1102704 N/A N/A 34277 34296 AAAGACAGAACCTAGAGAGA  83 2215 1102705 N/A N/A 34287 34306 CCAAGCTCCCAAAGACAGAA  52 2216 1102706 N/A N/A 34304 34323 GCTTGATAACCTTAGACCCA  37 2217 1102707 N/A N/A 34402 34421 CAAATACTCAAAAAGGGAAA  47 2218 1102708 N/A N/A 34403 34422 TCAAATACTCAAAAAGGGAA  75 2219 1102709 N/A N/A 34405 34424 CTTCAAATACTCAAAAAGGG 107 2220 1102710 N/A N/A 34406 34425 GCTTCAAATACTCAAAAAGG  45 2221 1102711 N/A N/A 34407 34426 AGCTTCAAATACTCAAAAAG  69 2222 1102712 N/A N/A 34411 34430 ATGAAGCTTCAAATACTCAA  71 2223 1102713 N/A N/A 34424 34443 TACTATATTCAGTATGAAGC  33 2224 1102714 N/A N/A 34425 34444 TTACTATATTCAGTATGAAG  59 2225 1102715 N/A N/A 34427 34446 GATTACTATATTCAGTATGA  48 2226 1102716 N/A N/A 34429 34448 ATGATTACTATATTCAGTAT  52 2227 1102717 N/A N/A 34431 34450 CTATGATTACTATATTCAGT  31 2228 1102718 N/A N/A 34432 34451 ACTATGATTACTATATTCAG  38 2229 1102719 N/A N/A 34433 34452 TACTATGATTACTATATTCA  65 2230 1102720 N/A N/A 34436 34455 GAATACTATGATTACTATAT  37 2231 1102721 N/A N/A 34437 34456 TGAATACTATGATTACTATA  89 2232 1102722 N/A N/A 34440 34459 GCATGAATACTATGATTACT   6 2233 1102723 N/A N/A 34455 34474 TATGATTTTCTTTATGCATG   9 2234 1102724 N/A N/A 34456 34475 TTATGATTTTCTTTATGCAT  29 2235 1102725 N/A N/A 34465 34484 GCAATTACTTTATGATTTTC  12 2236 1102726 N/A N/A 34467 34486 ATGCAATTACTTTATGATTT  15 2237 1102727 N/A N/A 34468 34487 TATGCAATTACTTTATGATT  62 2238 1102728 N/A N/A 34469 34488 TTATGCAATTACTTTATGAT  72 2239 1102729 N/A N/A 34470 34489 TTTATGCAATTACTTTATGA 100 2240 1102730 N/A N/A 34486 34505 ATGATTACTTTATGCATTTA  91 2241 1102731 N/A N/A 34488 34507 CTATGATTACTTTATGCATT  57 2242 1102732 N/A N/A 34493 34512 GAAAACTATGATTACTTTAT  83 2243 1102733 N/A N/A 34494 34513 TGAAAACTATGATTACTTTA  65 2244 1102735 N/A N/A 34498 34517 TGCATGAAAACTATGATTAC  59 2245 1102737 N/A N/A 34511 34530 CTAGTTTTTTTAATGCATGA  34 2246 1102738 N/A N/A 34512 34531 ACTAGTTTTTTTAATGCATG  76 2247 1102739 N/A N/A 34513 34532 AACTAGTTTTTTTAATGCAT  74 2248 1102740 N/A N/A 34851 34870 ATAAATTATGAATCTGTAAT 108 2249 1102741 N/A N/A 34855 34874 ACTCATAAATTATGAATCTG  53 2250 1102742 N/A N/A 34856 34875 GACTCATAAATTATGAATCT  86 2251 1102743 N/A N/A 34857 34876 TGACTCATAAATTATGAATC  99 2252 1102744 N/A N/A 34861 34880 TTAATGACTCATAAATTATG 101 2253 1102745 N/A N/A 34877 34896 GGCTTGAAAATATTATTTAA  83 2254 1102746 N/A N/A 34894 34913 GCTGGAAAAAATGTCATGGC  40 2255 1102747 N/A N/A 34895 34914 TGCTGGAAAAAATGTCATGG  45 2256 1102748 N/A N/A 34917 34936 GTAAAACAGATTTAGAGACT  68 2257 1102749 N/A N/A 34919 34938 TGGTAAAACAGATTTAGAGA  36 2258 1102750 N/A N/A 34971 34990 GGTTTTACAGTGACACAGCT  19 2259 1102751 N/A N/A 35004 35023 TTGCTTAATTTCATGCTTCT  71 2260 1102752 N/A N/A 35021 35040 AAATAGTTTCACACACATTG  27 2261 1102753 N/A N/A 35023 35042 TAAAATAGTTTCACACACAT  63 2262 1102754 N/A N/A 35025 35044 TATAAAATAGTTTCACACAC  69 2263 1102755 N/A N/A 35061 35080 AACTGCCAACATGTATGTAT  42 2264 1102756 N/A N/A 35094 35113 CATTTCAAAGCCACACCTAG 106 2265 1102757 N/A N/A 35098 35117 CATCCATTTCAAAGCCACAC  44 2266 1102758 N/A N/A 35174 35193 TGTCCATGAAGATATTTGTG  31 2267 1102759 N/A N/A 35185 35204 ATAGCAATCCATGTCCATGA  10 2268 1102760 N/A N/A 35186 35205 CATAGCAATCCATGTCCATG  22 2269 1102761 N/A N/A 35187 35206 TCATAGCAATCCATGTCCAT  38 2270 1102762 N/A N/A 35203 35222 TTAGGCAATCAAACACTCAT  73 2271 1102763 N/A N/A 35240 35259 TAAATTATACCATATCACTG  88 2272 1102764 N/A N/A 35243 35262 TGATAAATTATACCATATCA 110 2273 1102765 N/A N/A 35247 35266 TGTTTGATAAATTATACCAT  79 2274 1102766 N/A N/A 35264 35283 TTTCTGTTTCTCAACACTGT  77 2275 1102767 N/A N/A 35286 35305 CTCTTTAAAACATCCCCAGT  95 2276 1102768 N/A N/A 35290 35309 TTTCCTCTTTAAAACATCCC  37 2277 1102769 N/A N/A 35321 35340 TATGTAAACCCCTAATTTCT 100 2278 1102771 N/A N/A 35332 35351 TTTCTTAAGATTATGTAAAC 146 2279 1102773 N/A N/A 35440 35459 TTTAATATCCTCATTACCCA  52 2280 1102774 N/A N/A 35441 35460 ATTTAATATCCTCATTACCC  77 2281 1102775 N/A N/A 35442 35461 AATTTAATATCCTCATTACC  71 2282 1102776 N/A N/A 35446 35465 CTTAAATTTAATATCCTCAT  67 2283 1102777 N/A N/A 35448 35467 TTCTTAAATTTAATATCCTC  75 2284 1102778 N/A N/A 35450 35469 TGTTCTTAAATTTAATATCC  50 2285 1102779 N/A N/A 35484 35503 GCTTTCTATGCCAAGGATCA  36 2286 1102780 N/A N/A 35562 35581 AGTCCCAAAATTCTGCTTCA 127 2287 1102781 N/A N/A 35566 35585 TGCCAGTCCCAAAATTCTGC  94 2288 1102782 N/A N/A 35588 35607 GCAAGCAAAGCCATTTGGGA  80 2289 1102783 N/A N/A 36442 36461 CTAAAAATACAAACCTTGTC  73 2290 1102784 N/A N/A 36582 36601 CATGAGCTTTAAAAAGCAGA 153 2291 1102785 N/A N/A 36603 36622 TGGTTACAAATTAAGTGCTC  79 2292 1102786 N/A N/A 36604 36623 CTGGTTACAAATTAAGTGCT  64 2293 1102787 N/A N/A 36606 36625 TTCTGGTTACAAATTAAGTG  37 2294 1102788 N/A N/A 36624 36643 ATTATTTTACAAGTAGGATT  86 2295 1102789 N/A N/A 36627 36646 TAGATTATTTTACAAGTAGG  15 2296 1102790 N/A N/A 36628 36647 TTAGATTATTTTACAAGTAG  65 2297 1102791 N/A N/A 36629 36648 CTTAGATTATTTTACAAGTA  55 2298 1102792 N/A N/A 36634 36653 CATGTCTTAGATTATTTTAC  38 2299 1102793 N/A N/A 36658 36677 TAGAGGTTACAAAGCTAAAA  31 2300 1102794 N/A N/A 36670 36689 CCATCAATATTATAGAGGTT   7 2301 1102795 N/A N/A 36734 36753 TCCAGCTGTGAAGACACTGA 103 2302 1102796 N/A N/A 36757 36776 ACCTTGAAACAATGTAGACA  71 2303 1102797 N/A N/A 36797 36816 ACTTTTAGTTTATGAAAAAT  96 2304 1102798 N/A N/A 36799 36818 CTACTTTTAGTTTATGAAAA 105 2305 1102799 N/A N/A 36804 36823 TTATTCTACTTTTAGTTTAT  75 2306 1102800 N/A N/A 36807 36826 CCTTTATTCTACTTTTAGTT  53 2307 1102801 N/A N/A 36808 36827 GCCTTTATTCTACTTTTAGT  22 2308 1102802 N/A N/A 36811 36830 ATAGCCTTTATTCTACTTTT  17 2309 1102803 N/A N/A 36815 36834 AGGAATAGCCTTTATTCTAC  57 2310 1102804 N/A N/A 36817 36836 AGAGGAATAGCCTTTATTCT  51 2311 1102805 N/A N/A 36830 36849 AGATAGCAATTTTAGAGGAA  30 2312 1102807 N/A N/A 36973 36992 CCCATTAGCAAATCCTGATG  72 2313 1102809 N/A N/A 37096 37115 AGAAAGTTCAACTAATGAGA  87 2314 1102810 N/A N/A 37124 37143 TTTTGTGTTTTAAAACTGTG  61 2315 1102811 N/A N/A 37153 37172 TGGCACATTTTTTATAGAGT   4 2316 1102812 N/A N/A 37171 37190 CAACAATTATTAATAGAATG  81 2317 1102813 N/A N/A 37172 37191 GCAACAATTATTAATAGAAT  77 2318 1102814 N/A N/A 37173 37192 AGCAACAATTATTAATAGAA 109 2319 1102815 N/A N/A 37174 37193 CAGCAACAATTATTAATAGA  48 2320 1102816 N/A N/A 37176 37195 ACCAGCAACAATTATTAATA  55 2321 1102817 N/A N/A 37177 37196 TACCAGCAACAATTATTAAT 106 2322 1102818 N/A N/A 37185 37204 TTTTAAATTACCAGCAACAA  71 2323 1102819 N/A N/A 37187 37206 ATTTTTAAATTACCAGCAAC  52 2324 1102820 N/A N/A 37191 37210 AAGGATTTTTAAATTACCAG  35 2325 1102821 N/A N/A 37194 37213 AACAAGGATTTTTAAATTAC  81 2326 1102822 N/A N/A 37317 37336 GCTGACAATCTCAGTGAGAA  76 2327 1102823 N/A N/A 37321 37340 AACAGCTGACAATCTCAGTG  58 2328 1102824 N/A N/A 37330 37349 AAACTTACAAACAGCTGACA  66 2329 1102825 N/A N/A 37332 37351 CAAAACTTACAAACAGCTGA  58 2330 1102826 N/A N/A 37341 37360 ACCAAAAACCAAAACTTACA  89 2331 1102827 N/A N/A 37342 37361 AACCAAAAACCAAAACTTAC  84 2332 1102828 N/A N/A 37437 37456 CTAAAAAACCCCAAATCTAA  87 2333 1102829 N/A N/A 37438 37457 CCTAAAAAACCCCAAATCTA 104 2334 1102830 N/A N/A 37439 37458 TCCTAAAAAACCCCAAATCT  75 2335 1102831 N/A N/A 37448 37467 ATTCACAAATCCTAAAAAAC  92 2336 1102832 N/A N/A 37454 37473 GCAAATATTCACAAATCCTA  30 2337 1102833 N/A N/A 37456 37475 GTGCAAATATTCACAAATCC  30 2338 1102834 N/A N/A 37457 37476 AGTGCAAATATTCACAAATC  27 2339 1102835 N/A N/A 37459 37478 ATAGTGCAAATATTCACAAA  33 2340 1102836 N/A N/A 37535 37554 CATGATACTCAAAAGAGGTG  85 2341 1102837 N/A N/A 37597 37616 CATCCTAAATCCGAGAATCA 100 2342 1102838 N/A N/A 37601 37620 CAAGCATCCTAAATCCGAGA  90 2343 1102839 N/A N/A 37618 37637 AATCTGAAATTACAGGTCAA  89 2344 1102840 N/A N/A 37620 37639 TAAATCTGAAATTACAGGTC  90 2345 1102841 N/A N/A 37633 37652 TTCTGCTTTTATGTAAATCT  20 2346 1102843 N/A N/A 37711 37730 CATATTATTCCCAAATGGTT  53 2347 1102845 N/A N/A 37762 37781 ACTTAGAAAATATACACTGA  82 2348 1102846 N/A N/A 37764 37783 GTACTTAGAAAATATACACT  43 2349 1102847 N/A N/A 37779 37798 TAGGAATATATTCTTGTACT  37 2350 1102848 N/A N/A 37783 37802 TATGTAGGAATATATTCTTG  25 2351 1102849 N/A N/A 37816 37835 TAAAATGTTTAAACATGACG  78 2352 1102850 N/A N/A 37825 37844 TCCCCATTTTAAAATGTTTA  79 2353 1102851 N/A N/A 37834 37853 TAATACAAATCCCCATTTTA  78 2354 1102852 N/A N/A 37838 37857 AATGTAATACAAATCCCCAT  58 2355 1102853 N/A N/A 37900 37919 ATCAGATTTTAAGTAATACT  85 2356 1102854 N/A N/A 37903 37922 ATTATCAGATTTTAAGTAAT  87 2357 1102855 N/A N/A 37906 37925 CACATTATCAGATTTTAAGT  69 2358 1102856 N/A N/A 37907 37926 ACACATTATCAGATTTTAAG  48 2359 1102857 N/A N/A 37908 37927 CACACATTATCAGATTTTAA  67 2360 1102858 N/A N/A 37913 37932 TTTAACACACATTATCAGAT  67 2361 1102859 N/A N/A 37917 37936 ACTATTTAACACACATTATC  85 2362 1102860 N/A N/A 37919 37938 CTACTATTTAACACACATTA  65 2363 1102861 N/A N/A 37922 37941 AAACTACTATTTAACACACA  60 2364 1102862 N/A N/A 37923 37942 AAAACTACTATTTAACACAC 107 2365 1102863 N/A N/A 37927 37946 AATGAAAACTACTATTTAAC  84 2366 1102864 N/A N/A 38009 38028 TATCTTACTCATCTATTTCC  70 2367 1102865 N/A N/A 38053 38072 TATTTCCCTCTTTATGGCAT  36 2368 1102866 N/A N/A 38116 38135 CCCATTATTTCATCACTTCA  42 2369 1102867 N/A N/A 38123 38142 TGACATTCCCATTATTTCAT  64 2370 1102868 N/A N/A 38146 38165 CCATCCCACCAAAAGTAGCC  86 2371 1102869 N/A N/A 38183 38202 AGCTTAAAATTTATCTCCCC  69 2372 1102870 N/A N/A 38184 38203 GAGCTTAAAATTTATCTCCC  60 2373 1102871 N/A N/A 38225 38244 ATAATGTTTCCATGGCTGGC  69 2374 1102872 N/A N/A 38234 38253 TGAGTTAACATAATGTTTCC  45 2375 1102873 N/A N/A 38236 38255 TGTGAGTTAACATAATGTTT  53 2376 1102874 N/A N/A 38247 38266 TCAAACTACCATGTGAGTTA  93 2377 1102875 N/A N/A 38251 38270 CATTTCAAACTACCATGTGA 101 2378 1102876 N/A N/A 38252 38271 GCATTTCAAACTACCATGTG  46 2379 1102877 N/A N/A 38255 38274 AAAGCATTTCAAACTACCAT  48 2380 1102879 N/A N/A 38286 38305 AGTCACCAAAAATAAGTACC  66 2381 1102881 N/A N/A 38294 38313 TTGTTGAAAGTCACCAAAAA  65 2382 1102882 N/A N/A 38304 38323 ACCCTTAATATTGTTGAAAG  54 2383 1102883 N/A N/A 38306 38325 AGACCCTTAATATTGTTGAA  53 2384 1102884 N/A N/A 38311 38330 TTTATAGACCCTTAATATTG  82 2385 1102885 N/A N/A 38357 38376 TACAAAAAGATTCACTGGTA  59 2386 1102886 N/A N/A 38359 38378 CATACAAAAAGATTCACTGG  93 2387 1102887 N/A N/A 38362 38381 TATCATACAAAAAGATTCAC  70 2388 1102888 N/A N/A 38364 38383 CCTATCATACAAAAAGATTC  76 2389 1102889 N/A N/A 38368 38387 AAAACCTATCATACAAAAAG  92 2390 1102890 N/A N/A 38374 38393 AAACAAAAAACCTATCATAC 105 2391 1102891 N/A N/A 38681 38700 AATAACCTATCATGGCCAGG  66 2392 1102892 N/A N/A 38686 38705 CACAAAATAACCTATCATGG  94 2393 1102893 N/A N/A 38687 38706 TCACAAAATAACCTATCATG  70 2394 1102894 N/A N/A 38689 38708 CATCACAAAATAACCTATCA  75 2395 1102895 N/A N/A 38690 38709 TCATCACAAAATAACCTATC  81 2396 1102896 N/A N/A 38691 38710 TTCATCACAAAATAACCTAT  65 2397 1102897 N/A N/A 38692 38711 TTTCATCACAAAATAACCTA  64 2398 1102898 N/A N/A 38715 38734 CAGACAAATTAAGAGGTAGG  21 2399 1102899 N/A N/A 38717 38736 ATCAGACAAATTAAGAGGTA  47 2400 1102900 N/A N/A 38718 38737 TATCAGACAAATTAAGAGGT  48 2401 1102901 N/A N/A 38724 38743 TAAATTTATCAGACAAATTA 106 2402 1102902 N/A N/A 38726 38745 TTTAAATTTATCAGACAAAT  90 2403 1102903 N/A N/A 38727 38746 ATTTAAATTTATCAGACAAA  62 2404 1102904 N/A N/A 38730 38749 AAAATTTAAATTTATCAGAC 102 2405 1102905 N/A N/A 38732 38751 ATAAAATTTAAATTTATCAG 115 2406 1102906 N/A N/A 38736 38755 AGACATAAAATTTAAATTTA 106 2407 1102907 N/A N/A 38738 38757 CTAGACATAAAATTTAAATT  89 2408 1102908 N/A N/A 38773 38792 TACTTTAAAATATGGAAGTG  85 2409 1102909 N/A N/A 38777 38796 AGATTACTTTAAAATATGGA 108 2410 1102910 N/A N/A 38785 38804 TCTGATACAGATTACTTTAA  66 2411 1102911 N/A N/A 38787 38806 AGTCTGATACAGATTACTTT  54 2412 1102912 N/A N/A 38812 38831 GTATTAAAAGAATGCAAGAG  57 2413 1102913 N/A N/A 38817 38836 CACTGGTATTAAAAGAATGC  66 2414 1102915 N/A N/A 38852 38871 TAAGGAAAATACATTGTTTC  80 2415 1102917 N/A N/A 38868 38887 TGAGAAAAACTATTCATAAG  86 2416 1102918 N/A N/A 38869 38888 ATGAGAAAAACTATTCATAA  97 2417 1102919 N/A N/A 38872 38891 ACCATGAGAAAAACTATTCA  64 2418 1102920 N/A N/A 38879 38898 TAAATACACCATGAGAAAAA 101 2419 1102921 N/A N/A 38880 38899 ATAAATACACCATGAGAAAA  68 2420 1102922 N/A N/A 38882 38901 GAATAAATACACCATGAGAA  98 2421 1102923 N/A N/A 38884 38903 AAGAATAAATACACCATGAG  98 2422 1102924 N/A N/A 38885 38904 AAAGAATAAATACACCATGA  81 2423 1102925 N/A N/A 38886 38905 AAAAGAATAAATACACCATG 109 2424 1102926 N/A N/A 38890 38909 ACTTAAAAGAATAAATACAC  83 2425 1102927 N/A N/A 38913 38932 GTGAAGTATATTTAAAAAAC  74 2426 1102928 N/A N/A 38927 38946 TGAAACATTCAAAAGTGAAG  87 2427 1102929 N/A N/A 38933 38952 GCTGTCTGAAACATTCAAAA  79 2428 1100520*  986 1005 38992 39011 ACTCTGTCCTGATAGGTCCC  17 2429 1100521*  988 1007 38994 39013 GAACTCTGTCCTGATAGGTC  12 2430 1100522* 1030 1049 39036 39055 CCAAGTGCTCCTGAACTGGT  19 2431 1100523* 1040 1059 39046 39065 TAGATCACTCCCAAGTGCTC  17 2432 1100524* 1043 1062 39049 39068 ACCTAGATCACTCCCAAGTG  16 2433 1100525* 1044 1063 N/A N/A CACCTAGATCACTCCCAAGT  18 2434 1100526* 1046 1065 N/A N/A ATCACCTAGATCACTCCCAA  20 2435 1100527* 1047 1066 N/A N/A CATCACCTAGATCACTCCCA  12 2436 1100528* 1049 1068 N/A N/A AGCATCACCTAGATCACTCC  10 2437 1100529* 1050 1069 N/A N/A TAGCATCACCTAGATCACTC  24 2438 1100530* 1052 1071 N/A N/A CATAGCATCACCTAGATCAC  21 2439 1100531* 1082 1101 45608 45627 CACAGCTGCCTGAAGCATGT  70 2440 1100532* 1083 1102 45609 45628 TCACAGCTGCCTGAAGCATG  19 2441 1100533* 1084 1103 45610 45629 GTCACAGCTGCCTGAAGCAT  15 2442 1100534* 1085 1104 45611 45630 GGTCACAGCTGCCTGAAGCA   4 2443 1100535* 1086 1105 45612 45631 TGGTCACAGCTGCCTGAAGC   6 2444 1100536* 1087 1106 45613 45632 ATGGTCACAGCTGCCTGAAG  13 2445 1100538* 1089 1108 45615 45634 ACATGGTCACAGCTGCCTGA  20 2446 1100540* 1091 1110 45617 45636 AGACATGGTCACAGCTGCCT   7 2447 1100541* 1092 1111 45618 45637 AAGACATGGTCACAGCTGCC  11 2448 1100542* 1093 1112 45619 45638 AAAGACATGGTCACAGCTGC  10 2449 1100543* 1094 1113 45620 45639 TAAAGACATGGTCACAGCTG  19 2450 1100544* 1095 1114 45621 45640 CTAAAGACATGGTCACAGCT  15 2451 1100545* 1098 1117 45624 45643 TTTCTAAAGACATGGTCACA  50 2452 1100546* 1099 1118 45625 45644 GTTTCTAAAGACATGGTCAC  19 2453 1100547* 1102 1121 45628 45647 ACAGTTTCTAAAGACATGGT  35 2454 1100548* 1103 1122 45629 45648 GACAGTTTCTAAAGACATGG  81 2455 1100549* 1104 1123 45630 45649 TGACAGTTTCTAAAGACATG  47 2456 1100550* 1105 1124 45631 45650 CTGACAGTTTCTAAAGACAT  34 2457 1100551* 1106 1125 45632 45651 TCTGACAGTTTCTAAAGACA  36 2458 1100552* 1111 1130 45637 45656 TCATTTCTGACAGTTTCTAA  24 2459 1100553* 1114 1133 45640 45659 AAATCATTTCTGACAGTTTC  29 2460 1100554* 1115 1134 45641 45660 CAAATCATTTCTGACAGTTT  27 2461 1100555* 1118 1137 45644 45663 TTTCAAATCATTTCTGACAG  28 2462 1100556* 1119 1138 45645 45664 TTTTCAAATCATTTCTGACA  53 2463 1102930* N/A N/A 39053 39072 CCTTACCTAGATCACTCCCA  52 2464 1102931* N/A N/A 39126 39145 AAAGCAAAAATCACATGGAG  58 2465 1102932* N/A N/A 39144 39163 GGGAATGAAGAATAATGTAA  24 2466 1102933* N/A N/A 39162 39181 TCTTAATATGATTAAAGAGG  61 2467 1102934* N/A N/A 39163 39182 TTCTTAATATGATTAAAGAG 100 2468 1102935* N/A N/A 39184 39203 AGATTACAAATTTACTTAAG  54 2469 1102936* N/A N/A 39185 39204 TAGATTACAAATTTACTTAA 116 2470 1102937* N/A N/A 39187 39206 AGTAGATTACAAATTTACTT  94 2471 1102938* N/A N/A 39192 39211 AATTTAGTAGATTACAAATT  85 2472 1102939* N/A N/A 39200 39219 TCCAGGGAAATTTAGTAGAT  16 2473 1102940* N/A N/A 39207 39226 TCCTTAATCCAGGGAAATTT  75 2474 1102941* N/A N/A 39213 39232 AACTGCTCCTTAATCCAGGG  22 2475 1102942* N/A N/A 39215 39234 GTAACTGCTCCTTAATCCAG  36 2476 1102943* N/A N/A 39307 39326 TTCTAGCAATCCTCTCCTGC  74 2477 1102944* N/A N/A 39339 39358 TTAAATTATTATGTTAAAGT 100 2478 1102945* N/A N/A 39340 39359 TTTAAATTATTATGTTAAAG  87 2479 1102946* N/A N/A 39341 39360 GTTTAAATTATTATGTTAAA  96 2480 1102947* N/A N/A 39342 39361 AGTTTAAATTATTATGTTAA 114 2481 1102948* N/A N/A 39343 39362 AAGTTTAAATTATTATGTTA  92 2482 1102949* N/A N/A 39344 39363 GAAGTTTAAATTATTATGTT  86 2483 1102951* N/A N/A 39347 39366 TGTGAAGTTTAAATTATTAT  98 2484 1102953* N/A N/A 39362 39381 GACTGTACAAATTACTGTGA  48 2485 1102954* N/A N/A 39364 39383 GAGACTGTACAAATTACTGT  67 2486 1102955* N/A N/A 39704 39723 TACTAATATTCATGATTTCT  66 2487 1102956* N/A N/A 39705 39724 CTACTAATATTCATGATTTC  76 2488 1102957* N/A N/A 39710 39729 TTCACCTACTAATATTCATG  35 2489 1102958* N/A N/A 39711 39730 TTTCACCTACTAATATTCAT  82 2490 1102959* N/A N/A 39713 39732 TTTTTCACCTACTAATATTC  82 2491 1102960* N/A N/A 39714 39733 ATTTTTCACCTACTAATATT 104 2492 1102961* N/A N/A 39753 39772 CTCAAGTATTTTTCATTTTC  72 2493 1102962* N/A N/A 39760 39779 GATTATACTCAAGTATTTTT  66 2494 1102963* N/A N/A 39762 39781 TAGATTATACTCAAGTATTT  66 2495 1102964* N/A N/A 39763 39782 TTAGATTATACTCAAGTATT  62 2496 1102965* N/A N/A 39764 39783 TTTAGATTATACTCAAGTAT  72 2497 1102966* N/A N/A 39767 39786 TTATTTAGATTATACTCAAG  79 2498 1102967* N/A N/A 39769 39788 TGTTATTTAGATTATACTCA  56 2499 1102968* N/A N/A 39774 39793 CCCATTGTTATTTAGATTAT  55 2500 1102969* N/A N/A 39815 39834 AGACATATTTAAACCGAGAC  15 2501 1102970* N/A N/A 39816 39835 AAGACATATTTAAACCGAGA   8 2502 1102971* N/A N/A 39817 39836 TAAGACATATTTAAACCGAG  16 2503 1102972* N/A N/A 39818 39837 TTAAGACATATTTAAACCGA  71 2504 1102973* N/A N/A 39833 39852 CTAATTGGCCAAAGTTTAAG  57 2505 1102974* N/A N/A 39844 39863 AACTTCTACTACTAATTGGC  37 2506 1102975* N/A N/A 39850 39869 TCTCTCAACTTCTACTACTA  39 2507 1102976* N/A N/A 39851 39870 TTCTCTCAACTTCTACTACT  60 2508 1102977* N/A N/A 39860 39879 AGTTACTTTTTCTCTCAACT  11 2509 1102978* N/A N/A 39883 39902 TGCTTATAATTTCTTTGTCA  10 2510 1102979* N/A N/A 39884 39903 CTGCTTATAATTTCTTTGTC  10 2511 1102980* N/A N/A 39885 39904 TCTGCTTATAATTTCTTTGT  11 2512 1102981* N/A N/A 39944 39963 CCTTCACCTTTTTATTGAGT  37 2513 1102982* N/A N/A 39952 39971 TTTCAAATCCTTCACCTTTT  43 2514 1102983* N/A N/A 39954 39973 CTTTTCAAATCCTTCACCTT 121 2515 1102984* N/A N/A 39958 39977 ATATCTTTTCAAATCCTTCA  44 2516 1102985* N/A N/A 40088 40107 TTCATTAAAGCCATACCTAC  88 2517 1102987* N/A N/A 40171 40190 TACACTTTTACATTCCCATT  16 2518 1102989* N/A N/A 40206 40225 TTATCAAAAAAATGCCAAAC 103 2519 1102990* N/A N/A 40207 40226 TTTATCAAAAAAATGCCAAA 111 2520 1102991* N/A N/A 40208 40227 ATTTATCAAAAAAATGCCAA  71 2521 1102992* N/A N/A 40210 40229 ACATTTATCAAAAAAATGCC  84 2522 1102993* N/A N/A 40211 40230 TACATTTATCAAAAAAATGC  80 2523 1102994* N/A N/A 40216 40235 AAGTATACATTTATCAAAAA  86 2524 1102995* N/A N/A 40284 40303 TATGTGAACCTAAGTTTTCT  61 2525 1102996* N/A N/A 40296 40315 GATATAAGTTTTTATGTGAA  34 2526 1102997* N/A N/A 40957 40976 AAGGTCTACATTTAGGCAGT  75 2527 1102998* N/A N/A 40979 40998 TTGTGCATTCATTAACTAAA  14 2528 1102999* N/A N/A 41041 41060 AGGAATAGAAAAAAGTACCA  58 2529 1103000* N/A N/A 41058 41077 GGCTGTACTTAAACAGGAGG  31 2530 1103001* N/A N/A 41083 41102 TTTTATACAAATGTTGAGGT  14 2531 1103002* N/A N/A 41085 41104 TGTTTTATACAAATGTTGAG  91 2532 1103003* N/A N/A 41089 41108 CTCATGTTTTATACAAATGT  64 2533 1103004* N/A N/A 41486 41505 AAGAAAATCCAGTCCACTCC  64 2534 1103005* N/A N/A 41488 41507 AAAAGAAAATCCAGTCCACT  56 2535 1103006* N/A N/A 41609 41628 TCTAAAGGTTTTTATCTTGC  31 2536 1103007* N/A N/A 41616 41635 CTTATTATCTAAAGGTTTTT  68 2537 1103008* N/A N/A 41731 41750 AGAAGTGTACCTTATGACTT  50 2538 1103009* N/A N/A 41812 41831 AGTGTTATCACCTCCTGGAG 106 2539 1103010* N/A N/A 41814 41833 GGAGTGTTATCACCTCCTGG  63 2540 1103011* N/A N/A 41881 41900 CAGAGAGATGCCTATGTATT  42 2541 1103012* N/A N/A 42140 42159 GGAGTGAAAGTCCAGGTTTC  30 2542 1103013* N/A N/A 42220 42239 CATCTTCCAATTTAGCAAGC  82 2543 1103014* N/A N/A 42232 42251 GAATCTTATTTACATCTTCC  12 2544 1103015* N/A N/A 42233 42252 TGAATCTTATTTACATCTTC  27 2545 1103016* N/A N/A 42234 42253 GTGAATCTTATTTACATCTT  28 2546 1103017* N/A N/A 42236 42255 ATGTGAATCTTATTTACATC  79 2547 1103018* N/A N/A 42280 42299 ATTTTCAATTAAATCCTGAA  66 2548 1103019* N/A N/A 42283 42302 GTGATTTTCAATTAAATCCT  70 2549 1103020* N/A N/A 42579 42598 CTGACACAAATTTAGATGGA  64 2550 1103021* N/A N/A 42764 42783 CAGTGTTCAGAAATCTGACT  87 2551 1103023* N/A N/A 42864 42883 CCTTCTGGCCTTTATGATCT  69 2552 1103025* N/A N/A 43501 43520 GAGAAATTCCTTTAGCCATT  16 2553 1103026* N/A N/A 43502 43521 AGAGAAATTCCTTTAGCCAT  28 2554 1103027* N/A N/A 43503 43522 TAGAGAAATTCCTTTAGCCA  19 2555 1103028* N/A N/A 43504 43523 TTAGAGAAATTCCTTTAGCC  30 2556 1103029* N/A N/A 43537 43556 CCAAAATTACTTCTTTTATC  46 2557 1103030* N/A N/A 43539 43558 TTCCAAAATTACTTCTTTTA  67 2558 1103031* N/A N/A 43540 43559 GTTCCAAAATTACTTCTTTT  15 2559 1103032* N/A N/A 43541 43560 TGTTCCAAAATTACTTCTTT  43 2560 1103033* N/A N/A 43542 43561 ATGTTCCAAAATTACTTCTT  95 2561 1103034* N/A N/A 43545 43564 CTGATGTTCCAAAATTACTT  52 2562 1103035* N/A N/A 43576 43595 TTTTACTCTTTTTATTGTTC  37 2563 1103036* N/A N/A 43582 43601 CCCATATTTTACTCTTTTTA  30 2564 1103037* N/A N/A 43584 43603 TACCCATATTTTACTCTTTT  50 2565 1103038* N/A N/A 43620 43639 TAGAAAATTCAAAAGGAGGG  90 2566 1103039* N/A N/A 43632 43651 CATCATACAATTTAGAAAAT 112 2567 1103040* N/A N/A 43642 43661 TTGCTTCAACCATCATACAA  56 2568 1103041* N/A N/A 43651 43670 CTATAATTCTTGCTTCAACC  19 2569 1103042* N/A N/A 43670 43689 ACTGAAAACCAAATCAGTGC  91 2570 1103043* N/A N/A 43672 43691 ATACTGAAAACCAAATCAGT  98 2571 1103044* N/A N/A 43675 43694 TATATACTGAAAACCAAATC 156 2572 1103045* N/A N/A 43693 43712 CCTTAAATATTTCCAATATA  73 2573 1103046* N/A N/A 43699 43718 ATAATGCCTTAAATATTTCC  33 2574 1103047* N/A N/A 43734 43753 CCCTTTATATCCTTTGACCC  46 2575 1103048* N/A N/A 43741 43760 GTTACCTCCCTTTATATCCT  32 2576 1103049* N/A N/A 43744 43763 AAGGTTACCTCCCTTTATAT  69 2577 1103050* N/A N/A 43746 43765 GAAAGGTTACCTCCCTTTAT  82 2578 1103051* N/A N/A 43747 43766 AGAAAGGTTACCTCCCTTTA  73 2579 1103052* N/A N/A 43755 43774 AGAAATATAGAAAGGTTACC  93 2580 1103053* N/A N/A 43768 43787 GCATCAGTACAAAAGAAATA  86 2581 1103054* N/A N/A 43795 43814 ATAGTGAAATTATTTTCCAA  53 2582 1103055* N/A N/A 43807 43826 GTTTTTAAACAAATAGTGAA  95 2583 1103056* N/A N/A 43811 43830 TTCAGTTTTTAAACAAATAG  91 2584 1103057* N/A N/A 43812 43831 GTTCAGTTTTTAAACAAATA  48 2585 1103059* N/A N/A 44052 44071 TTCAGCAATTAAAGACTTTT  48 2586 1103061* N/A N/A 44073 44092 CAAATATTAGCCAAAGAGGC  90 2587 1103062* N/A N/A 44396 44415 ATAATGATCTTCCAGGCTGG 138 2588 1103063* N/A N/A 44400 44419 CTAAATAATGATCTTCCAGG 105 2589 1103064* N/A N/A 44404 44423 AGGACTAAATAATGATCTTC  45 2590 1103065* N/A N/A 44548 44567 ATATAAATTTCTATTTTTGG  81 2591 1103066* N/A N/A 44549 44568 AATATAAATTTCTATTTTTG 112 2592 1103067* N/A N/A 44674 44693 CAGTAGAGTATTACATGCTA  29 2593 1103068* N/A N/A 44688 44707 CTTTTTAATCCTGACAGTAG  63 2594 1103069* N/A N/A 44693 44712 GGTTTCTTTTTAATCCTGAC  89 2595 1103070* N/A N/A 44695 44714 TGGGTTTCTTTTTAATCCTG  76 2596 1103071* N/A N/A 44733 44752 CCCCTGAGATCCAGCCACGG  90 2597 1103072* N/A N/A 44809 44828 AGCTGTCATTTTTAGTTGAA  31 2598 1103073* N/A N/A 44826 44845 GTTCTCTATCTCTATACAGC  19 2599 1103074* N/A N/A 44844 44863 AGTGGAAACCACTAATATGT  79 2600 1103075* N/A N/A 44861 44880 ACCCACTTTCTCTAACTAGT  69 2601 1103076* N/A N/A 44897 44916 CTGCTATCGATTTATATTCC  99 2602 1103077* N/A N/A 44920 44939 GTTATAATACCACAAAGATC  26 2603 1103078* N/A N/A 44921 44940 TGTTATAATACCACAAAGAT  80 2604 1103079* N/A N/A 44923 44942 AGTGTTATAATACCACAAAG  52 2605 1103080* N/A N/A 44924 44943 AAGTGTTATAATACCACAAA  76 2606 1103081* N/A N/A 44925 44944 GAAGTGTTATAATACCACAA  33 2607 1103082* N/A N/A 44932 44951 AGACATAGAAGTGTTATAAT  61 2608 1103083* N/A N/A 44940 44959 TACAATCAAGACATAGAAGT  76 2609 1103084* N/A N/A 44984 45003 TACATGGCATTTTATCACAC  32 2610 1103085* N/A N/A 44997 45016 TTATATGTAGTTCTACATGG  62 2611 1103086* N/A N/A 45032 45051 CAAACTAAAACCTAGATATT  90 2612 1103087* N/A N/A 45035 45054 GATCAAACTAAAACCTAGAT  76 2613 1103088* N/A N/A 45036 45055 AGATCAAACTAAAACCTAGA  91 2614 1103089* N/A N/A 45038 45057 AAAGATCAAACTAAAACCTA  74 2615 1103090* N/A N/A 45041 45060 ACTAAAGATCAAACTAAAAC 101 2616 1103091* N/A N/A 45043 45062 TAACTAAAGATCAAACTAAA 113 2617 1103092* N/A N/A 45044 45063 GTAACTAAAGATCAAACTAA 100 2618 1103093* N/A N/A 45077 45096 TTTGCCCAATTTCACCCAAT  46 2619 1103095* N/A N/A 45114 45133 AGTTGTAAAGATATTTAAGA  86 2620 1103097* N/A N/A 45155 45174 AAACCCAACTTTCTATTTTG  57 2621 1103098* N/A N/A 45161 45180 TTACAAAAACCCAACTTTCT  86 2622 1103099* N/A N/A 45162 45181 TTTACAAAAACCCAACTTTC  79 2623 1103100* N/A N/A 45165 45184 GTATTTACAAAAACCCAACT  45 2624 1103101* N/A N/A 45167 45186 ATGTATTTACAAAAACCCAA  57 2625 1103102* N/A N/A 45172 45191 AATTCATGTATTTACAAAAA  76 2626 1103103* N/A N/A 45184 45203 GTGTATATCAACAATTCATG   8 2627 1103104* N/A N/A 45186 45205 TTGTGTATATCAACAATTCA  65 2628 1103105* N/A N/A 45313 45332 GATAGCCACCAGTATATTCT  75 2629 1103106* N/A N/A 45316 45335 CCAGATAGCCACCAGTATAT  41 2630 1103107* N/A N/A 45332 45351 TCCCCATTTCCTAATCCCAG  96 2631 1103108* N/A N/A 45370 45389 CCCCAGAAAATTCCCCCATG  85 2632 1103109* N/A N/A 45390 45409 GATACACAACCATTCCATTG  68 2633 1103110* N/A N/A 45395 45414 ATCAAGATACACAACCATTC  63 2634 1103111* N/A N/A 45410 45429 TTTGACAAATACACCATCAA  68 2635 1103112* N/A N/A 45421 45440 GTTCTATATATTTTGACAAA  47 2636 1103113* N/A N/A 45423 45442 TAGTTCTATATATTTTGACA  38 2637 1103114* N/A N/A 45426 45445 TTATAGTTCTATATATTTTG  73 2638 1103115* N/A N/A 45430 45449 ACTTTTATAGTTCTATATAT 104 2639 1103116* N/A N/A 45473 45492 CACGAGTTTCTTTTTTTGAT  20 2640 1103117* N/A N/A 45491 45510 AATGTATTTCTATTTGAGCA  40 2641 1103118* N/A N/A 45520 45539 CAAAGTCATCAAAAGGCAAG  86 2642 1103119* N/A N/A 45525 45544 ATTCTCAAAGTCATCAAAAG  84 2643 1103120* N/A N/A 45529 45548 GAAAATTCTCAAAGTCATCA  99 2644 1103121* N/A N/A 45534 45553 TTCCAGAAAATTCTCAAAGT  95 2645 1103122* N/A N/A 45548 45567 CATTTCTTTAAAATTTCCAG  92 2646 1103123* N/A N/A 45552 45571 ACCACATTTCTTTAAAATTT  88 2647 1103124* N/A N/A 45559 45578 AAACAAAACCACATTTCTTT 102 2648 1103125* N/A N/A 45560 45579 GAAACAAAACCACATTTCTT 100 2649 1103126* N/A N/A 45561 45580 GGAAACAAAACCACATTTCT 108 2650 1103127* N/A N/A 45562 45581 GGGAAACAAAACCACATTTC  80 2651 1103128* N/A N/A 45564 45583 TTGGGAAACAAAACCACATT 100 2652 1103129* N/A N/A 45565 45584 GTTGGGAAACAAAACCACAT  94 2653

TABLE 3 Percent control of human ATXN3 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID No: 1 No: 1 No: 2 No: 2 ATXN3 SEQ Compound Start Stop Start Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO 1100368  312  331 16178 16197 CCCAAACTTTCAAGGCATTG  31  169 1100368  312  331 16178 16197 CCCAAACTTTCAAGGCATTG  30  169 1100404  407  426 16700 16719 GTGTTCCTTATAATTGCATA  32  203 1100404  407  426 16700 16719 GTGTTCCTTATAATTGCATA  31  203 1100440  515  534 21242 21261 TAATTGAGCCAAGAAAAGTG  96  237 1100440  515  534 21242 21261 TAATTGAGCCAAGAAAAGTG 130  237 1100476  711  730 27568 27587 TTCCTGAGCCATCATTTGCT  62  271 1100476  711  730 27568 27587 TTCCTGAGCCATCATTTGCT  71  271 1100512  886  905 28981 29000 TCTGAAGTAAGATTTGTACC  57  305 1100512  886  905 28981 29000 TCTGAAGTAAGATTTGTACC  95  305 1100548 1103 1122 45629 45648 GACAGTTTCTAAAGACATGG  62 2455 1100584 1244 1263 45770 45789 AAGTCTTATTTCCTCATCTC  18  338 1100584 1244 1263 45770 45789 AAGTCTTATTTCCTCATCTC  16  338 1100620 1619 1638 46145 46164 GAACCATTACTATTATCAAC  31  372 1100620 1619 1638 46145 46164 GAACCATTACTATTATCAAC  35  372 1100656 1807 1826 46333 46352 AGTCATGAAATAATGATCCC  76  406 1100656 1807 1826 46333 46352 AGTCATGAAATAATGATCCC  59  406 1100692 2047 2066 46573 46592 TAGTCTTCTAACAGAAGGAG  81  440 1100728 2236 2255 46762 46781 TCATGTTCCAGATCACCATC  38  474 1100728 2236 2255 46762 46781 TCATGTTCCAGATCACCATC  34  474 1100764 2386 2405 46912 46931 AATTAAAGAGAATATTTATC  95  508 1100764 2386 2405 46912 46931 AATTAAAGAGAATATTTATC  96  508 1100800 2570 2589 47096 47115 GAAGTTGTCAGCTGAAATTT  35  542 1100800 2570 2589 47096 47115 GAAGTTGTCAGCTGAAATTT  38  542 1100836 2744 2763 47270 47289 AATGACTTAAAAAATCTGTT  84  576 1100836 2744 2763 47270 47289 AATGACTTAAAAAATCTGTT  85  576 1100872 2927 2946 47453 47472 CAGTCTTAAAATATTTAGCT  19  610 1100872 2927 2946 47453 47472 CAGTCTTAAAATATTTAGCT  14  610 1100908 3062 3081 47588 47607 TCTCATTTTTATATTAGGTA  31  644 1100908 3062 3081 47588 47607 TCTCATTTTTATATTAGGTA  20  644 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   8   45 1100914 3074 3093 47600 47619 GCATATTGGTTTTCTCATTT   9   45 1100945 3555 3574 48081 48100 TCACAACAAACTACACAAAC  77  678 1100945 3555 3574 48081 48100 TCACAACAAACTACACAAAC  70  678 1100981 3682 3701 48208 48227 CTGGCATCTTTTCATACTGG  37  712 1100981 3682 3701 48208 48227 CTGGCATCTTTTCATACTGG  33  712 1101017 3874 3893 48400 48419 TATTAAACATTAAGATGTTC  78  746 1101017 3874 3893 48400 48419 TATTAAACATTAAGATGTTC  88  746 1101053 3935 3954 48461 48480 GTACATACTTGATCCCAGTA  20  780 1101053 3935 3954 48461 48480 GTACATACTTGATCCCAGTA  16  780 1101089 4022 4041 48548 48567 AAAACATAAATTACTCATTA 102  814 1101089 4022 4041 48548 48567 AAAACATAAATTACTCATTA 100  814 1101125 4170 4189 48696 48715 AATTGTAAATTATTTGGCCA  78  848 1101125 4170 4189 48696 48715 AATTGTAAATTATTTGGCCA  62  848 1101161 4834 4853 49360 49379 CTACTTAAGATTTTAAAATT  96  882 1101161 4834 4853 49360 49379 CTACTTAAGATTTTAAAATT 137  882 1101197 5992 6011 50518 50537 TAATTAGGGTCACATATATA  70  916 1101197 5992 6011 50518 50537 TAATTAGGGTCACATATATA 113  916 1101233 6228 6247 50754 50773 ATCAAAATTCTAGAATTTAC  92  950 1101233 6228 6247 50754 50773 ATCAAAATTCTAGAATTTAC  72  950 1101269 6563 6582 51089 51108 CAGTGTTGTAAAAATTAGAT  81  984 1101269 6563 6582 51089 51108 CAGTGTTGTAAAAATTAGAT  78  984 1101305 6764 6783 51290 51309 GTGTGTGTAATAACAGCAAA  75 1018 1101305 6764 6783 51290 51309 GTGTGTGTAATAACAGCAAA  89 1018 1101341   96  115 13165 13184 GAGCACAAAGTGAGCCTTCT  60 1052 1101341   96  115 13165 13184 GAGCACAAAGTGAGCCTTCT  91 1052 1101377  229  248 13298 13317 GTGCGATAATCTTCACTAGT  82 1086 1101377  229  248 13298 13317 GTGCGATAATCTTCACTAGT  85 1086 1101413 N/A N/A 51449 51468 ACACAAATTCAAAAGGAAAT  91 1116 1101413 N/A N/A 51449 51468 ACACAAATTCAAAAGGAAAT  85 1116 1101593 N/A N/A  4174  4193 CACTCCTAATACCTAAAAAC  97 1166 1101593 N/A N/A  4174  4193 CACTCCTAATACCTAAAAAC 119 1166 1101629 N/A N/A  5365  5384 GCCTTTGAAAATTAATAACA  89 1200 1101629 N/A N/A  5365  5384 GCCTTTGAAAATTAATAACA  86 1200 1101665 N/A N/A  6667  6686 TGACAGAGACTACAGCTGGC  91 1234 1101665 N/A N/A  6667  6686 TGACAGAGACTACAGCTGGC  76 1234 1101701 N/A N/A  7486  7505 ACACTACTAACTACAACACA  87 1268 1101701 N/A N/A  7486  7505 ACACTACTAACTACAACACA 117 1268 1101737 N/A N/A  8823  8842 TCAGTACAAATTTAAAAATC  84 1302 1101737 N/A N/A  8823  8842 TCAGTACAAATTTAAAAATC 102 1302 1101773 N/A N/A  9341  9360 TTCCAGTCACAAAAGCTCAA  59 1336 1101773 N/A N/A  9341  9360 TTCCAGTCACAAAAGCTCAA  57 1336 1101809 N/A N/A 10463 10482 TACTGAATAATATGCAAATT 107 1370 1101809 N/A N/A 10463 10482 TACTGAATAATATGCAAATT  98 1370 1101845 N/A N/A 11711 11730 CCCTAGAACATTTATTCTTT  84 1404 1101845 N/A N/A 11711 11730 CCCTAGAACATTTATTCTTT  86 1404 1101881 N/A N/A 13129 13148 AGAAAAAATTAAAATGTGAC  80 1438 1101881 N/A N/A 13129 13148 AGAAAAAATTAAAATGTGAC 105 1438 1101917 N/A N/A 14390 14409 AAGGAATTTTTAAATGCCCC  70 1472 1101917 N/A N/A 14390 14409 AAGGAATTTTTAAATGCCCC  72 1472 1101953 N/A N/A 15441 15460 CTGGGCATTTAAACTGAAGG  59 1506 1101953 N/A N/A 15441 15460 CTGGGCATTTAAACTGAAGG  46 1506 1101989 N/A N/A 16110 16129 CCATTCCAAATTTAGGAAGT  92 1540 1101989 N/A N/A 16110 16129 CCATTCCAAATTTAGGAAGT  73 1540 1102025 N/A N/A 17173 17192 TTCCTAATTTTAAAGTCAGC  33 1574 1102025 N/A N/A 17173 17192 TTCCTAATTTTAAAGTCAGC  43 1574 1102061 N/A N/A 17584 17603 CTTGCTCAAGACATATTTCA  60 1608 1102061 N/A N/A 17584 17603 CTTGCTCAAGACATATTTCA  52 1608 1102097 N/A N/A 19126 19145 CCAGAGGTTAAATAATCTCA  56 1642 1102097 N/A N/A 19126 19145 CCAGAGGTTAAATAATCTCA  47 1642 1102133 N/A N/A 19460 19479 ACAATGTTAATACTTTTTCC  50 1676 1102133 N/A N/A 19460 19479 ACAATGTTAATACTTTTTCC  63 1676 1102169 N/A N/A 20122 20141 TGTCAAAAGATTCCAATTGT  65 1710 1102169 N/A N/A 20122 20141 TGTCAAAAGATTCCAATTGT  62 1710 1102205 N/A N/A 21101 21120 TTAAGAATAGATACAACCCA  80 1744 1102205 N/A N/A 21101 21120 TTAAGAATAGATACAACCCA  89 1744 1102241 N/A N/A 22464 22483 TTTATGTTATTTTTTAGCCA  86 1778 1102241 N/A N/A 22464 22483 TTTATGTTATTTTTTAGCCA  77 1778 1102277 N/A N/A 23289 23308 AGAGACAATCCTAAGGAAAA  83 1812 1102277 N/A N/A 23289 23308 AGAGACAATCCTAAGGAAAA  90 1812 1102313 N/A N/A 24093 24112 TTAGGAAAACCACAGCATGG  84 1846 1102313 N/A N/A 24093 24112 TTAGGAAAACCACAGCATGG  78 1846 1102349 N/A N/A 25507 25526 CCAGAAATCCAGGGTTTCCC  62 1880 1102349 N/A N/A 25507 25526 CCAGAAATCCAGGGTTTCCC  92 1880 1102385 N/A N/A 26322 26341 TCTTGGTTTCTACTGTTAAA  21 1914 1102385 N/A N/A 26322 26341 TCTTGGTTTCTACTGTTAAA  22 1914 1102421 N/A N/A 27036 27055 TAATATATTTAAGTATTTCA  77 1948 1102421 N/A N/A 27036 27055 TAATATATTTAAGTATTTCA 115 1948 1102457 N/A N/A 27887 27906 AAAAATATAACTACTCCTAA  83 1982 1102457 N/A N/A 27887 27906 AAAAATATAACTACTCCTAA  59 1982 1102493 N/A N/A 28293 28312 AAATAATTTCATTAGAAAGT  89 2016 1102493 N/A N/A 28293 28312 AAATAATTTCATTAGAAAGT  80 2016 1102529 N/A N/A 29028 29047 AACTACTTTACTTTTCAAAG  81 2050 1102529 N/A N/A 29028 29047 AACTACTTTACTTTTCAAAG 104 2050 1102565 N/A N/A 30354 30373 AGAATGGATGAAATACAGCA  53 2084 1102565 N/A N/A 30354 30373 AGAATGGATGAAATACAGCA  81 2084 1102601 N/A N/A 30610 30629 TTAGCCATTAATCTATACTG  34 2118 1102601 N/A N/A 30610 30629 TTAGCCATTAATCTATACTG  32 2118 1102637 N/A N/A 32676 32695 GCCAAAATACTAACATCAGT  25 2152 1102637 N/A N/A 32676 32695 GCCAAAATACTAACATCAGT  33 2152 1102673 N/A N/A 33921 33940 TGTTTACTAAAAAGCACTAG  65 2186 1102673 N/A N/A 33921 33940 TGTTTACTAAAAAGCACTAG  98 2186 1102709 N/A N/A 34405 34424 CTTCAAATACTCAAAAAGGG  63 2220 1102709 N/A N/A 34405 34424 CTTCAAATACTCAAAAAGGG  63 2220 1102745 N/A N/A 34877 34896 GGCTTGAAAATATTATTTAA  83 2254 1102745 N/A N/A 34877 34896 GGCTTGAAAATATTATTTAA  89 2254 1102781 N/A N/A 35566 35585 TGCCAGTCCCAAAATTCTGC  83 2288 1102781 N/A N/A 35566 35585 TGCCAGTCCCAAAATTCTGC  95 2288 1102817 N/A N/A 37177 37196 TACCAGCAACAATTATTAAT  67 2322 1102817 N/A N/A 37177 37196 TACCAGCAACAATTATTAAT  68 2322 1102853 N/A N/A 37900 37919 ATCAGATTTTAAGTAATACT  66 2356 1102853 N/A N/A 37900 37919 ATCAGATTTTAAGTAATACT  94 2356 1102889 N/A N/A 38368 38387 AAAACCTATCATACAAAAAG  95 2390 1102889 N/A N/A 38368 38387 AAAACCTATCATACAAAAAG 108 2390 1102925 N/A N/A 38886 38905 AAAAGAATAAATACACCATG  84 2424 1102925 N/A N/A 38886 38905 AAAAGAATAAATACACCATG 102 2424 1102961 N/A N/A 39753 39772 CTCAAGTATTTTTCATTTTC  45 2493 1102997 N/A N/A 40957 40976 AAGGTCTACATTTAGGCAGT  38 2527 1103033 N/A N/A 43542 43561 ATGTTCCAAAATTACTTCTT  52 2561 1103069 N/A N/A 44693 44712 GGTTTCTTTTTAATCCTGAC  13 2595 1103105 N/A N/A 45313 45332 GATAGCCACCAGTATATTCT  32 2629 1100548* 1103 1122 45629 45648 GACAGTTTCTAAAGACATGG  47 2455 1100692* 2047 2066 46573 46592 TAGTCTTCTAACAGAAGGAG  58 440 1102961* N/A N/A 39753 39772 CTCAAGTATTTTTCATTTTC  46 2493 1102997* N/A N/A 40957 40976 AAGGTCTACATTTAGGCAGT  34 2527 1103033* N/A N/A 43542 43561 ATGTTCCAAAATTACTTCTT  50 2561 1103069* N/A N/A 44693 44712 GGTTTCTTTTTAATCCTGAC  14 2595 1103105* N/A N/A 45313 45332 GATAGCCACCAGTATATTCT  35 2629

TABLE 4 Percent control of human ATXN3 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ ID Com- ID No: ATXN3 pound No: 3 3 (% SEQ Num- Start Stop Sequence con- ID ber Site Site (5′ to 3′) trol) NO 1100366 88 107 GCATTGCTTATAACTTTCTC 63 2654 1100367 89 108 GGCATTGCTTATAACTTTCT 49 2655

TABLE 5 Percent control of human ATXN3 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ ID Com- ID No: ATXN3 pound No: 4 4 (% SEQ Num- Start Stop Sequence con- ID ber Site Site (5′ to 3′) trol) NO 1101399 291 310 TAAACCACTGAATAGAGAAA  91 2656 1101400 294 313 AGTTAAACCACTGAATAGAG  76 2657 1101401 295 314 AAGTTAAACCACTGAATAGA 107 2658 1101402 297 316 TCAAGTTAAACCACTGAATA  65 2659 1101403 298 317 TTCAAGTTAAACCACTGAAT  90 2660 1101404 300 319 AATTCAAGTTAAACCACTGA  89 2661

TABLE 6 Percent control of human ATXN3 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ ID Com- ID No: ATXN3 pound No: 5 5 (% SEQ Num- Start Stop Sequence con- ID ber Site Site (5′ to 3′) trol) NO 1101448  9782  9801 CAAAGCAGTTAAATCTGGCC  96 2662 1101449 10192 10211 TGGGTTTATATATTTTTCTT  72 2663 1101449 10192 10211 TGGGTTTATATATTTTTCTT 100 2663 1101449 10192 10211 TGGGTTTATATATTTTTCTT 111 2663 1101450 10194 10213 TGTGGGTTTATATATTTTTC  78 2664 1101451 10235 10254 TAATCCAATGAATGCATCTC  79 2665 1101452 10588 10607 AAGTCACTGTTATATTAGTT 201 2666 1101453 10595 10614 GCATGTAAAGTCACTGTTAT 121 2667 1101454 10609 10628 AAAAAAAACCCATAGCATGT 109 2668 1101455 10610 10629 GAAAAAAAACCCATAGCATG  89 2669 1101456 10611 10630 AGAAAAAAAACCCATAGCAT  81 2670 1101457 10615 10634 GAGGAGAAAAAAAACCCATA  95 2671 1101458 10630 10649 ATTTCTTGAAGATGAGAGGA  99 2672 1101459 10683 10702 AGCAGATTCCTGACACTGTG 110 2673 1101460 10684 10703 GAGCAGATTCCTGACACTGT 118 2674 1101461 10697 10716 AATTATACAGAAAGAGCAGA  84 2675 1101462 10699 10718 ACAATTATACAGAAAGAGCA 127 2676 1101463 10701 10720 TAACAATTATACAGAAAGAG  95 2677 1101464 10702 10721 GTAACAATTATACAGAAAGA  99 2678 1101465 10703 10722 TGTAACAATTATACAGAAAG 109 2679 1101466 10704 10723 CTGTAACAATTATACAGAAA 124 2680 1101467 10705 10724 CCTGTAACAATTATACAGAA  71 2681 1101468 10706 10725 TCCTGTAACAATTATACAGA  90 2682 1101469 11124 11143 AGGATGAGATACAAGGTCAA 108 2683 1101470 11556 11575 ACATAAAGCCATTATGTCAG  91 2684 1101471 11557 11576 TACATAAAGCCATTATGTCA  96 2685 1101472 11558 11577 GTACATAAAGCCATTATGTC  74 2686 1101473 11564 11583 AGCCATGTACATAAAGCCAT 105 2687 1101474 12097 12116 AAAAACCACCTTGTAGCTAG 107 2688 1101475 12100 12119 AATAAAAACCACCTTGTAGC  86 2689 1101476 12101 12120 GAATAAAAACCACCTTGTAG  79 2690 1101477 12102 12121 AGAATAAAAACCACCTTGTA  77 2691 1101478 12103 12122 CAGAATAAAAACCACCTTGT  77 2692 1101479 12105 12124 CCCAGAATAAAAACCACCTT  72 2693 1101480 12106 12125 ACCCAGAATAAAAACCACCT  89 2694 1101481 12113 12132 CATGGCAACCCAGAATAAAA  88 2695 1101482 12114 12133 GCATGGCAACCCAGAATAAA  94 2696 1101483 12502 12521 CTGGAACACTTTTAAAAAAT  87 2697 1101484 12535 12554 TTTCTTACTCCCCTATGCCC  95 2698 1101485 12541 12560 TTCCACTTTCTTACTCCCCT  87 2699 1101485 12541 12560 TTCCACTTTCTTACTCCCCT 110 2699 1101485 12541 12560 TTCCACTTTCTTACTCCCCT  93 2699 1101486 12542 12561 TTTCCACTTTCTTACTCCCC  79 2700 1101487 12626 12645 ATGTGAATATCCTGCCTCCA 111 2701 1101488 12688 12707 ACCTTATTCAGCCAGAGTTG  92 2702 1101489 12691 12710 GCAACCTTATTCAGCCAGAG  79 2703 1101490 12725 12744 GCCCATACTTTCCAGGTGCC  77 2704 1101491 12727 12746 GAGCCCATACTTTCCAGGTG 102 2705 1101492 12732 12751 TACTGGAGCCCATACTTTCC  98 2706 1101493 12785 12804 CCCTTTACCACTTTTGTGCA  70 2707 1101494 12788 12807 CATCCCTTTACCACTTTTGT  81 2708 1101495 12827 12846 CATGACAGCCAAGATGCCAG  87 2709 1101496 12938 12957 TTAGCATTTCTCTTCTGTTG  78 2710 1101497 13356 13375 TGTTGCTTTCCTTTCCTGCA  97 2711 1101498 13395 13414 GATTTCAGTCTACATCTAAC 111 2712 1101499 13399 13418 TCCTGATTTCAGTCTACATC  88 2713 1101500 13402 13421 ACCTCCTGATTTCAGTCTAC  96 2714 1101501 13414 13433 AGTTTTAACCACACCTCCTG  91 2715 1101502 13418 13437 AAAGAGTTTTAACCACACCT  92 2716 1101503 13428 13447 AGCCTCTTTCAAAGAGTTTT  90 2717 1101504 13917 13936 TCTGAAATTAATAATGGTGT 117 2718 1101505 13919 13938 GCTCTGAAATTAATAATGGT  89 2719 1101506 13968 13987 GCCTTGTTTTCTTCCAAGAA 119 2720 1101507 14062 14081 ACAAAACATCAAGAATTCTA  92 2721 1101508 14064 14083 CAACAAAACATCAAGAATTC 101 2722 1101509 14065 14084 TCAACAAAACATCAAGAATT 125 2723 1101510 14066 14085 TTCAACAAAACATCAAGAAT  86 2724 1101511 14069 14088 GTTTTCAACAAAACATCAAG 143 2725 1101512 14070 14089 TGTTTTCAACAAAACATCAA  86 2726 1101513 14074 14093 CTTCTGTTTTCAACAAAACA  94 2727 1101514 14076 14095 TGCTTCTGTTTTCAACAAAA  90 2728 1101515 14111 14130 GAATCTTTCTAAAACTTACC  62 2729 1101516 14112 14131 AGAATCTTTCTAAAACTTAC  81 2730 1101517 14115 14134 TACAGAATCTTTCTAAAACT  80 2731 1101518 14207 14226 GTACCAAGATTATATTGCCT  90 2732 1101519 14208 14227 TGTACCAAGATTATATTGCC  84 2733 1101520 14209 14228 TTGTACCAAGATTATATTGC 102 2734 1101521 14212 14231 ATGTTGTACCAAGATTATAT 116 2735 1101521 14212 14231 ATGTTGTACCAAGATTATAT  70 2735 1101521 14212 14231 ATGTTGTACCAAGATTATAT 130 2735 1101522 14214 14233 AAATGTTGTACCAAGATTAT  76 2736 1101523 14239 14258 AAGTCTTATTCATTGCAGCT  80 2737 1101524 14240 14259 TAAGTCTTATTCATTGCAGC  95 2738 1101525 14430 14449 TCTGAATTTCTAAGCATTAG  99 2739 1101526 14431 14450 TTCTGAATTTCTAAGCATTA  95 2740 1101527 14432 14451 TTTCTGAATTTCTAAGCATT  98 2741 1101528 14456 14475 GACTTTAAAATTTAGTCTGA  83 2742 1101529 14459 14478 GTAGACTTTAAAATTTAGTC  78 2743 1101530 14460 14479 AGTAGACTTTAAAATTTAGT  92 2744 1101531 14461 14480 AAGTAGACTTTAAAATTTAG  81 2745 1101532 14507 14526 TCAAAATGAATTTATTTATG  91 2746 1101533 14509 14528 CATCAAAATGAATTTATTTA  87 2747 1101534 14515 14534 GAAAACCATCAAAATGAATT 120 2748 1101535 14518 14537 TGAGAAAACCATCAAAATGA  63 2749 1101536 14519 14538 CTGAGAAAACCATCAAAATG 102 2750 1101537 14520 14539 TCTGAGAAAACCATCAAAAT 114 2751 1101538 14523 14542 TGTTCTGAGAAAACCATCAA 150 2752 1101539 14850 14869 TTTCCATTACTCAAGCAGTG  74 2753 1101540 15114 15133 AAAGACATACAAGTTTGATA 127 2754 1101541 15119 15138 AGTTAAAAGACATACAAGTT  83 2755 1101542 15120 15139 AAGTTAAAAGACATACAAGT 104 2756 1101543 15189 15208 TGGTGGGTACATAAGGTTCA 105 2757 1101544 15215 15234 AGGAACTGATAATTGTTGAA  86 2758 1101545 15232 15251 GTGAAACAAGAATTGTCAGG  91 2759 1101546 15333 15352 GCTTCAAAATAATGGAAGTT 107 2760 1101547 15334 15353 TGCTTCAAAATAATGGAAGT 107 2761 1101548 15335 15354 GTGCTTCAAAATAATGGAAG 106 2762 1101549 15336 15355 TGTGCTTCAAAATAATGGAA  90 2763 1101550 15337 15356 ATGTGCTTCAAAATAATGGA  75 2764 1101551 15379 15398 CTTAATAAATAATGTGATAA  94 2765 1101552 15381 15400 AACTTAATAAATAATGTGAT 100 2766 1101553 15382 15401 AAACTTAATAAATAATGTGA 124 2767 1101554 15441 15460 CTATGTCCTAAAAGTTTCTC  77 2768 1101555 15442 15461 GCTATGTCCTAAAAGTTTCT 136 2769 1101556 15455 15474 AATTAACATAAAAGCTATGT  84 2770 1101557 15457 15476 GTAATTAACATAAAAGCTAT  96 2771 1101557 15457 15476 GTAATTAACATAAAAGCTAT  79 2771 1101557 15457 15476 GTAATTAACATAAAAGCTAT 114 2771 1101558 15459 15478 AAGTAATTAACATAAAAGCT  86 2772 1101559 15472 15491 TAGTGCAGAAATTAAGTAAT  98 2773 1101560 15479 15498 GGATGGCTAGTGCAGAAATT 104 2774 1101561 15507 15526 CTAGTGCAGAAAATTAGAAG  96 2775 1101562 15513 15532 GGATAGCTAGTGCAGAAAAT  88 2776 1101563 15619 15638 AGAATGAGACATGTAAGTAT 107 2777 1101564 15627 15646 GGTGAAAAAGAATGAGACAT  69 2778 1101565 15631 15650 CCTGGGTGAAAAAGAATGAG  70 2779 1101566 15633 15652 CACCTGGGTGAAAAAGAATG 106 2780 1101567 16440 16459 AACAAAAATTATCTAGATCC  94 2781 1101568 16913 16932 GTTGAGTTTTTATATTTGAT  69 2782 1101569 16915 16934 GGGTTGAGTTTTTATATTTG  90 2783 1101570 19195 19214 AAGATACTACTATAGCATAG  88 2784 1101571 19196 19215 GAAGATACTACTATAGCATA  78 2785 1101572 19197 19216 GGAAGATACTACTATAGCAT 107 2786 1101573 19198 19217 TGGAAGATACTACTATAGCA  84 2787

Example 2: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human ATXN3 In Vitro, Multiple Doses

Modified oligonucleotides selected from the examples above were tested at various doses in A431 cells by free uptake. Compound No. 650528, described in WO 2018/089805, was also tested. Compound No. 650528 is a 5-8-5 MOE gapmer, having a sequence (from 5′ to 3′) GCATCTTTTCATACTGGC (incorporated herein as SEQ ID NO: 2788), wherein each cytosine is a 5-methyl cytosine, each internucleoside linkage is either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage and the internucleoside linkage motif is s000sssssssssooss, where ‘s’ represents a phosphorothioate internucleoside linkage and ‘o’ represents a phosphodiester internucleoside linkage, and each of nucleosides 1-5 and 14-18 comprise a 2′-O-methyoxyethyl group.

Cells were plated at a density of 10,000 cells per well with 109.4 nM, 437.5 nM, 1,750.0 nM, and 7,000.0 nM concentrations of modified oligonucleotide, as specified in the tables below. After a treatment period of approximately 48 hours, total RNA was isolated from the cells and ATXN3 RNA levels were measured by RT-qPCR Human ATXN3 primer probe set RTS38920 (described hereinabove in Example 1) was used to measure RNA levels. ATXN3 RNA levels were adjusted according to total RNA content, as measured by RiboGreen®. Results are presented in the table below as percent ATXN3 RNA levels relative to untreated control cells. As illustrated in the table below, ATXN3 RNA levels were reduced in a dose-dependent manner in modified oligonucleotide-treated cells. IC₅₀ was calculated using the “log(inhibitor) vs. response—variable slope (4 parameters)” formula using Prism6 software.

TABLE 7 Dose-dependent reduction of human ATXN3 RNA by modified oligonucleotides ATXN3 level (% control) Compound 109.4 437.5 1,750.0 7,000.0 IC₅₀ Number nM nM nM nM (μM) 650528 100 57 39 30 1.3 1100379 77 66 37 23 0.9 1100384 86 64 35 25 1.0 1100397 68 49 25 15 0.4 1100398 63 46 26 14 0.3 1100399 81 39 39 22 0.6 1100403 61 48 32 20 0.3 1100405 60 41 25 16 0.2 1100406 85 45 24 12 0.5 1100407 56 27 15 8 0.1 1100408 61 45 21 13 0.3 1100409 56 34 19 12 0.1 1100410 69 64 38 27 0.8 1100429 89 65 38 24 1.1 1100430 90 72 53 30 1.9 1100434 77 51 30 18 0.6 1100468 72 61 44 36 1.3 1100475 68 52 28 21 0.5 1100479 89 89 56 34 2.9 1100557 77 63 47 36 1.5 1100559 76 53 29 18 0.6 1100560 56 45 27 20 0.2 1100566 64 34 13 7 0.2 1100567 68 50 31 22 0.5 1100568 97 71 41 30 1.6 1100571 97 79 38 25 1.5 1100572 79 74 45 30 1.5 1100574 78 68 46 24 1.2 1100580 102 74 43 27 1.6 1100583 54 46 26 12 0.2 1100584 61 42 23 10 0.2 1100585 67 48 25 15 0.4 1100589 74 53 32 20 0.6 1100590 78 39 17 6 0.4 1100591 71 46 26 16 0.4 1100592 82 86 56 57 >7.0 1100597 73 47 26 18 0.4 1100641 121 95 78 66 >7.0 1100666 71 48 31 20 0.5 1100667 80 53 38 25 0.8 1100668 78 62 39 26 1.0 1100669 75 41 23 14 0.4 1100673 55 25 15 10 <0.1 1100697 59 49 27 20 0.3 1100719 72 60 28 15 0.6 1100725 53 30 17 10 <0.1 1100729 86 70 44 38 1.9 1100730 58 41 25 16 0.2 1100732 62 43 23 22 0.3 1100753 60 52 33 30 0.4 1100756 60 48 35 29 0.3 1100768 76 52 32 19 0.6 1100788 88 72 48 30 1.7 1100789 90 67 56 40 2.8 1100796 63 48 37 26 0.4 1100802 50 34 23 19 <0.1 1100809 56 44 21 19 0.2 1100810 65 41 20 14 0.3 1100839 63 36 14 8 0.2 1100846 104 78 54 29 2.2 1100863 44 31 19 15 <0.1 1100864 67 35 19 16 0.2 1100865 56 34 18 13 0.1 1100872 65 40 23 13 0.3 1100873 46 36 18 12 <0.1 1100897 74 50 38 33 0.8 1100898 72 57 36 31 0.8 1100899 68 52 30 24 0.5 1100900 58 41 28 23 0.2 1100901 43 32 21 17 <0.1 1100902 58 35 24 19 0.2 1100903 72 53 32 24 0.6 1100906 56 42 26 16 0.2 1100907 26 26 15 12 <0.1 1100910 55 40 26 19 0.2 1100911 75 48 30 18 0.5 1100914 27 12 7 5 <0.1 1100914 26 11 6 5 <0.1 1100914 26 12 7 7 <0.1 1100914 29 11 6 5 <0.1 1100914 38 16 8 5 <0.1 1100914 34 13 7 5 <0.1 1100914 28 13 7 5 <0.1 1100914 27 13 6 5 <0.1 1100914 33 14 7 5 <0.1 1100914 33 12 6 6 <0.1 1100914 30 13 8 6 <0.1 1100914 28 15 8 6 <0.1 1100915 51 23 11 6 <0.1 1100916 35 22 14 12 <0.1 1100917 48 29 14 10 <0.1 1100920 46 30 15 9 <0.1 1100921 70 54 32 20 0.5 1100924 57 34 25 19 0.1 1100925 76 52 33 23 0.6 1100928 39 28 17 14 <0.1 1100980 51 39 25 16 0.1 1100988 62 41 27 22 0.3 1100989 64 38 22 14 0.2 1100990 36 25 13 12 <0.1 1100991 55 35 17 13 0.1 1100992 69 49 36 29 0.6 1100995 80 74 46 37 1.9 1100996 60 44 28 18 0.3 1100997 66 40 26 16 0.3 1100998 79 68 41 28 1.2 1100999 70 58 40 34 0.9 1101000 61 39 22 18 0.2 1101001 53 43 25 22 0.2 1101004 73 57 63 41 3.3 1101049 69 47 30 24 0.4 1101053 82 39 22 16 0.4 1101054 62 47 26 21 0.3 1101057 72 57 34 26 0.7 1101058 94 65 44 20 1.2 1101065 60 34 24 20 0.2 1101066 69 47 30 22 0.4 1101099 55 33 21 16 0.1 1101101 40 23 13 12 <0.1 1101120 66 50 37 30 0.5 1101121 71 54 36 20 0.6 1101122 77 48 33 25 0.6 1101201 60 54 36 34 0.5 1101202 35 21 15 13 <0.1 1101203 56 40 32 30 0.2 1101204 53 42 30 28 0.1 1101339 77 60 34 24 0.8 1101349 54 42 19 11 0.2 1101350 63 43 33 18 0.3 1101351 79 58 33 24 0.8 1101352 97 55 26 13 0.8 1101364 76 53 35 24 0.7 1101383 62 46 36 27 0.4 1101384 57 44 30 19 0.2 1101411 63 26 22 18 0.1 1101600 72 42 28 15 0.4 1101607 84 66 50 40 2.2 1101657 82 55 28 20 0.7 1101659 88 59 35 20 0.9 1101682 78 58 45 28 1.1 1101689 91 61 54 44 2.9 1101817 111 106 64 38 4.3 1101873 65 49 38 35 0.6 1101918 81 77 40 32 1.6 1101920 52 41 23 11 0.1 1101974 26 7 4 4 <0.1 1101975 32 15 7 5 <0.1 1102024 63 44 21 10 0.3 1102028 41 20 9 6 <0.1 1102049 61 45 30 19 0.3 1102050 61 27 13 8 0.1 1102052 63 51 32 26 0.4 1102074 41 21 12 6 <0.1 1102077 73 61 37 25 0.8 1102084 59 41 21 18 0.2 1102085 55 43 19 15 0.2 1102090 69 44 27 20 0.4 1102103 83 54 34 19 0.7 1102104 55 28 10 8 <0.1 1102108 79 67 45 21 1.1 1102110 87 48 26 14 0.6 1102119 109 109 76 60 >7.0 1102128 77 58 30 16 0.6 1102129 83 58 37 28 1.0 1102130 58 38 20 13 0.2 1102131 73 57 30 16 0.6 1102134 84 73 55 34 2.3 1102180 82 55 42 32 1.1 1102195 83 73 49 36 2.1 1102198 60 41 26 15 0.2 1102200 95 69 47 27 1.6 1102202 91 56 32 19 0.8 1102239 78 64 42 33 1.3 1102262 88 71 48 34 1.9 1102328 60 50 33 21 0.3 1102329 65 37 22 11 0.2 1102336 58 34 20 13 0.2 1102351 66 53 29 28 0.5 1102353 69 50 23 11 0.4 1102374 78 67 53 36 2.0 1102379 67 59 32 21 0.6 1102385 69 38 20 15 0.3 1102424 79 72 46 27 1.4 1102541 63 50 26 17 0.3 1102547 94 78 59 51 >7.0 1102551 87 50 23 11 0.6 1102552 67 51 30 28 0.5 1102557 74 35 21 10 0.3 1102562 73 60 35 20 0.7 1102563 64 49 36 22 0.4 1102573 82 46 26 18 0.6 1102574 61 43 24 17 0.2 1102579 62 59 32 22 0.5 1102580 67 46 26 16 0.4 1102598 93 54 26 14 0.7 1102599 66 47 23 11 0.3 1102600 77 56 35 22 0.7 1102612 71 51 35 24 0.6 1102637 92 63 37 21 1.1 1102646 75 56 35 30 0.8 1102655 82 83 55 38 3.1 1102657 71 39 18 12 0.3 1102663 63 55 38 27 0.5 1102666 58 30 15 9 0.1 1102667 73 50 26 15 0.5 1102668 88 64 44 32 1.5 1102669 67 68 48 32 1.4 1102677 68 49 27 20 0.4 1102678 65 35 25 17 0.2 1102679 72 58 48 36 1.3 1102683 55 45 31 17 0.2 1102684 82 44 20 12 0.5 1102690 68 60 36 33 0.8 1102695 90 53 27 18 0.7 1102722 67 39 20 9 0.3 1102723 71 48 28 21 0.5 1102725 48 37 23 10 <0.1 1102726 88 56 40 25 1.0 1102734 81 57 31 19 0.7 1102750 69 61 35 23 0.7 1102759 69 51 26 24 0.4 1102760 73 70 59 47 5.5 1102789 76 65 38 23 0.9 1102794 55 29 13 8 <0.1 1102801 80 56 36 29 0.9 1102802 77 56 28 23 0.6 1102811 29 16 8 6 <0.1 1102841 64 39 29 23 0.3

Example 3: Tolerability of Modified Oligonucleotides Complementary to Human ATXN3 in Wild-Type Mice

Modified oligonucleotides described above were tested in wild-type female C57/Bl6 mice to assess the tolerability of the oligonucleotides. Wild-type female C57/Bl6 mice each received a single ICV dose of 700 μs of modified oligonucleotide listed in the table below. Each treatment group consisted of 2 mice. A group of 2 mice received PBS as a negative control. At 3 hours post-injection, mice were evaluated according to 7 different criteria. The criteria are (1) the mouse was bright, alert, and responsive; (2) the mouse was standing or hunched without stimuli; (3) the mouse showed any movement without stimuli; (4) the mouse demonstrated forward movement after it was lifted; (5) the mouse demonstrated any movement after it was lifted; (6) the mouse responded to tail pinching; (7) regular breathing. For each of the 7 criteria, a mouse was given a subscore of 0 if it met the criteria and 1 if it did not (the functional observational battery score or FOB score). After all 7 criteria were evaluated, the scores were summed for each mouse and averaged within each treatment group. The results are presented in the table below.

TABLE 8 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 1100397 0.00 1100405 0.00 1100406 0.00 1100407 1.00 1100528 1.00 1100534 2.00 1100535 2.00 1100540 3.50 1100542 1.50 1100566 3.00 1100585 0.00 1100590 2.00 1100725 3.00 1100873 0.00 1100914 4.50 1100915 5.00 1100920 0.00 1100990 6.50 1100991 5.00 1101101 3.50 1101339 6.00 1101351 1.00 1101974 0.00 1101975 0.00 1102024 0.00 1102028 0.00 1102050 6.50 1102130 0.00 1102131 0.00 1102336 0.00 1102353 0.00 1102551 5.00 1102557 5.50 1102574 0.00 1102580 0.00 1102599 0.00 1102657 0.00 1102811 0.50 1102970 0.00 1102977 0.00 1102978 0.00 1102979 0.00 1103103 2.00

TABLE 9 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 1100379 0.00 1100398 1.00 1100399 3.00 1100409 4.00 1100521 4.00 1100527 1.00 1100536 3.00 1100541 4.00 1100544 4.00 1100571 3.00 1100572 2.00 1100667 5.50 1100673 1.00 1100730 3.00 1100732 3.00 1100809 1.00 1100864 2.00 1100865 1.00 1100907 4.00 1100911 1.00 1100980 4.00 1101054 2.00 1101065 4.00 1101121 3.00 1101122 2.00 1101350 3.00 1101352 3.00 1101411 1.00 1101657 1.00 1102084 2.00 1102090 3.00 1102128 3.00 1102198 1.00 1102562 3.00 1102563 3.00 1102612 3.00 1102667 1.00 1102677 3.00 1102683 1.00 1102684 1.00 1102725 2.50 1102980 1.00 1103001 3.00 1103014 1.00 1103069 2.00

Example 4: Activity of Modified Oligonucleotides Complementary to Human ATXN3 in Transgenic Mice

Modified oligonucleotides described above were tested in the ATXN3 YAC transgenic mouse model which contains the full-length human ATXN3 disease gene harboring an expanded CAG repeat (CAG₈₄, Q84). The hemizygous SCA3-Q84.2 mice are designated as wt/Q84 and were described in Costa Mdo C., et al., Toward RNAi Therapy for the Polyglutamine Disease Machado-Joseph Disease. Mol Ther, 2013. 21 (10): 1898-908.” Compound No. 650528, described hereinabove and in WO 2018/089805, was also tested

The ATXN3 transgenic mice were divided into groups of 3 mice each. Mice in each group were given a single ICV bolus of oligonucleotide at a dose of 300 μg and sacrificed two weeks later. A group of 4-6 mice was injected with PBS and served as the control group to which oligonucleotide-treated groups were compared. After two weeks, mice were sacrificed and RNA was extracted from brain tissue for real-time PCR analysis of measurement of RNA expression of ATXN3 using primer probe set RTS39540 (forward sequence CCTTCTTCCTGCGCCTTATT, designated herein as SEQ ID NO: 12; reverse sequence TCATGGTGGGTACGTATGTTTAG, designated herein as SEQ ID NO: 13; probe sequence AGTATGCAGGCAAGTCTCCTTCTGT, designated herein as SEQ ID NO: 14). Results are presented as percent change of RNA, relative to PBS control, normalized with cyclophilin A. As shown in the tables below, human ATXN3 RNA was reduced in various tissues.

TABLE 10 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 29 43 76 30 1100914 17 24 68 16 1100873 48 82 71 57 1100585 56 77 70 54 1100590 21 34 54 73 1102130 33 54 63 22 1102977 45 61 78 33 1102353 33 48 69 57 1102599 28 54 57 42 1102979 34 53 87 34 1102978 60 76 76 37 1101920 55 79 70 68 1100572 56 87 70 70 1100571 33 55 55 79 1100667 59 86 100 39

TABLE 11 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 25 42 71 29 1100914 15 19 56 17 1100528 71 67 80 68 1100915 27 27 46 27 1100397 49 58 60 52 1100406 55 58 69 51 1102050 41 46 67 37 1102024 47 41 72 51 1101101 31 37 71 34 1102551 56 62 76 61 1102574 29 40 60 30 1102970 64 60 85 68 1102336 53 42 68 58 1102811 16 22 40 17 1102028 25 25 59 23 1100434 78 75 84 78 1100559 53 41 76 50 1101121 40 46 61 37 1100992 45 49 56 41 1100468 58 59 74 53 1100544 81 62 88 73 1100810 57 95 65 47 1100379 55 54 66 52 1100673 9 12 67 11 1102669 72 69 81 70 1102725 50 49 76 50 1103014 50 52 70 40 1102667 55 111 72 58

TABLE 12 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 24 43 80 31 1100914 14 18 59 15 1100429 69 72 80 80 1100542 78 78 84 73 1100991 26 51 71 53 1100725 18 27 67 22 1102084 46 72 88 55 1101351 66 87 92 65 1102131 35 36 76 37 1103103 28 42 75 36 1102557 58 79 87 74 1102657 12 19 59 17 1100839 25 40 54 35 1100864 41 68 67 54 1100907 32 49 63 41

TABLE 13 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 24 37 93 31 1100914 14 22 68 19 1102108 61 54 88 63 1100697 44 48 75 39 1100902 38 45 83 39 1101383 52 65 101 65 1100900 46 62 92 56 1102562 45 54 64 55 1102637 30 29 50 34 1101203 52 65 70 68 1102612 33 47 73 39 1102198 51 75 96 66

TABLE 14 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 28 48 69 31 1100914 20 17 52 16 1102677 83 95 88 86 1102998 41 51 82 47 1103069 25 39 67 29 1100753 39 48 51 37

TABLE 15 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 23 38 74 30 1100914 13 15 50 18 1100920 76 86 104 84 1101352 68 84 93 69 1101099 54 68 101 62 1100990 15 41 60 22 1100872 53 65 81 62 1101122 30 23 61 31 1100898 34 37 84 34 1101918 69 93 71 71 1100405 49 58 98 45 1102580 56 79 85 49 1100407 50 63 91 50 1101054 29 31 75 36 1101350 56 74 78 64 1101975 31 58 70 38 1100921 64 86 83 65

TABLE 16 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 25 54 58 26 1100914 13 13 39 15 1100865 37 37 60 36 1100730 19 26 34 20 1100584 47 45 51 45 1101120 49 65 67 47 1100911 36 52 54 38 1102090 38 50 71 36 1102128 34 41 56 31 1100541 57 72 74 68 1100809 40 48 69 37 1102541 51 75 56 56 1102666 34 52 58 31 1100398 60 64 65 64 1100399 46 49 59 47 1100410 52 69 70 48 1100732 55 80 72 58

TABLE 17 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 21 38 67 26 1100914 14 18 43 16 1100557 53 78 78 74 1100980 23 45 80 24 1102600 48 55 86 44 1102980 41 43 67 43 1101657 17 23 57 19 1102684 65 85 110 73 1101202 28 33 66 27 1101659 29 39 77 27 1102103 36 43 81 41 1101873 41 49 80 41 1102202 69 78 98 70 1102180 68 72 106 75 1102239 63 68 92 82 1102678 73 79 92 77 1102052 68 83 100 72

TABLE 18 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem PBS 100 100 100 100 650528 28 35 83 27 1100914 13 11 46 12 1102129 28 26 56 20 1101053 42 56 97 43 1100430 81 75 76 78 1100666 50 44 70 47 1100756 45 64 71 42 1102598 33 31 56 30 1100863 52 53 77 52 1102646 63 80 87 62 1102750 59 66 70 57 1100802 29 36 61 36 1100906 44 46 69 52 1102379 64 69 94 72 1102663 60 83 63 69 1102679 80 93 92 92

Example 5: Tolerability of Modified Oligonucleotides Complementary to Human ATXN3 in Wild-Type Mice

Modified oligonucleotides described above were tested in wild-type female C57/Bl6 mice to assess the tolerability of the oligonucleotides. Wild-type female C57/Bl6 mice each received a single ICV dose of 700 μs of modified oligonucleotide listed in the table below. Each treatment group consisted of 4 mice. A group of 3-4 mice received PBS as a negative control. Also tested in several studies were comparator Compound No. 650528, a 5-8-5 MOE gapmer with mixed PO/PS internucleoside linkages complementary to human ATXN3 described hereinabove and in WO 2018/089805 and the following LNA comparator compounds: Compound No. 1244463 (a 3-9-3 LNA gapmer with uniform PS internucleoside linkages complementary to human ATXN3); Compound No. 1244464 (a 3-10-3 LNA gapmer with uniform PS internucleoside linkages complementary to human ATXN3); Compound No. 1244465 (a 3-10-3 LNA gapmer with uniform PS internucleoside linkages complementary to human ATXN3); Compound No. 1244466 (a 3-9-3 LNA gapmer with uniform PS internucleoside linkages complementary to human ATXN3); and Compound No. 1244467 (a 2-9-3 LNA gapmer with uniform PS internucleoside linkages complementary to human ATXN3), described in WO2013/138353 were tested.

At 3 hours post-injection, mice were evaluated according to 7 different criteria. The criteria are (1) the mouse was bright, alert, and responsive; (2) the mouse was standing or hunched without stimuli; (3) the mouse showed any movement without stimuli; (4) the mouse demonstrated forward movement after it was lifted; (5) the mouse demonstrated any movement after it was lifted; (6) the mouse responded to tail pinching; (7) regular breathing. For each of the 7 criteria, a mouse was given a subscore of 0 if it met the criteria and 1 if it did not (the functional observational battery score or FOB score). After all 7 criteria were evaluated, the scores were summed for each mouse and averaged within each treatment group. The results are presented in the table below.

TABLE 19 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 650528 0.00 1100559 4.00 1100802 5.75 1100839 4.25 1100898 0.00 1100914 5.25 1101202 5.25 1101659 1.50 1102129 2.75 1102598 0.00 1102637 3.50

TABLE 20 FOB scores in wild-type mice Compound 3 hour Number FOB 650528 0.00 1100408 6.25 1100673 0.00 1100725 4.50 1100730 2.75 1100914 4.00 1100917 6.00 1101000 4.75 1101122 3.25 1101657 0.00 1102130 0.00 1102131 0.75 1102574 1.00 1102811 2.25

TABLE 21 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 1100369 0.25 1100479 3.25 1100505 5.00 1100508 6.00 1101375 0.00 1101721 5.00 1101853 0.00  1102690* 0.00 1102706 1.00 1102808 1.75 1103041 3.00

TABLE 22 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 1101736 0.00

TABLE 23 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 1100505 4.00 1100506 1.50 1100672 0.00 1100731 1.25 1102811 2.25 1103041 3.25

TABLE 24 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 1100723 0.00 1100724 1.00 1100728 0.75 1100729 0.50

TABLE 25 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 1100506 2.00 1100731 3.75

TABLE 26 FOB scores in wild-type mice Compound 3 hour Number FOB PBS 0.00 1244463 7.00 1244464 7.00 1244465 7.00 1244466 7.00 1244467 7.00

Example 6: Activity of Modified Oligonucleotides Complementary to Human ATXN3 RNA in Transgenic Mice

Modified oligonucleotides were tested in the ATXN3 YAC transgenic mouse model which contains the full-length human ATXN3 disease gene harboring an expanded CAG repeat (CAG₈₄, Q84). The hemizygous SCA3-Q84.2 mice are designated as wt/Q84 and were described in Costa Mdo C., et al., Toward RNAi Therapy for the Polyglutamine Disease Machado-Joseph Disease. Mol Ther, 2013. 21 (10): 1898-908.

The ATXN3 transgenic mice were divided into groups of 2-3 mice each. Mice in each group were given a single ICV bolus of oligonucleotide at a dose of 300 μg and sacrificed two weeks later. A group of 2 to 5 mice was injected with PBS and served as the control group to which oligonucleotide-treated groups were compared. After two weeks, mice were sacrificed, and RNA was extracted from various regions of the central nervous system. ATXN3 RNA levels were measured by quantitative real-time RTPCR using human primer probe set RTS43981 (forward sequence TGACACAGACATCAGGTACAAATC, designated herein as SEQ ID NO: 2798; reverse sequence TGCTGCTGTTGCTGCTT, designated herein as SEQ ID NO: 2799; probe sequence AGCTTCGGAAGAGACGAGAAGCCTA, designated herein as SEQ ID NO: 2800). Results are presented as percent change of RNA, relative to PBS control, normalized to mouse cyclophilin A measured using mouse primer probe set m_cyclo24 (forward sequence TCGCCGCTTGCTGCA, designated herein as SEQ ID NO: 2801; reverse sequence ATCGGCCGTGATGTCGA, designated herein as SEQ ID NO: 2802; probe sequence CCATGGTCAACCCCACCGTGTTC, designated herein as SEQ ID NO: 2803). Also tested in several studies was comparator Compound No. 650528, a 5-8-5 MOE gapmer with mixed PO/PS internucleoside linkages complementary to human ATXN3 described hereinabove and in WO 2018/089805. As shown in the tables below, human ATXN3 RNA was reduced in various tissues

TABLE 27 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 38 41 79 40 1100408 28 40 68 32 1100409 30 55 59 36 1100521 68 87 83 74 1100527 76 83 79 82 1100534 57 71 97 59 1100535 77 96 100 84 1100536 76 103 80 90 1100540 67 69 89 68 1100566 68 94 85 74 1100673 17 14 53 16 1100914 23 17 50 24 1101000 34 37 69 34 1101065 43 62 66 42 1101339 51 56 78 57 1101411 29 52 56 30 1101974 17 22 50 19 1102329 46 48 73 49 1102563 42 45 78 41 1102657 20 18 52 19 1102683 27 29 60 27 1102811 27 38 66 23 1103001 45 53 71 52

TABLE 28 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 30 42 67 34 1100670 61 75 72 54 1100671 60 70 73 45 1100674 64 74 84 58 1100910 34 43 62 37 1100912 55 52 71 53 1100917 38 32 68 35

TABLE 29 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 39 61 81 38 1100505 32 38 64 34 1100522 59 85 89 64 1100523 88 103 83 96 1100597 63 85 85 71 1100914 22 29 63 28 1101349 45 70 71 52 1101370 67 107 97 71 1101600 41 47 70 44 1102328 39 57 66 37 1102794 51 71 86 62 1102939 63 63 87 76 1102941 50 80 84 60 1103073 44 73 68 51 1103116 44 63 78 47

TABLE 30 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 32 48 74 34 1100369 22 40 54 30 1100382 64 78 66 53 1100384 56 94 67 53 1100454 44 72 49 45 1101388 58 53 74 48 1101601 56 62 62 58 1101615 81 108 85 82 1101721 21 46 61 29 1101755 53 82 59 60 1101926 67 87 71 63 1101992 93 89 78 79 1102043 71 86 69 60 1102062 45 70 66 55 1102147 58 55 56 48 1102166 72 85 69 56 1102216 39 52 60 42 1102322 71 88 67 62 1102361 66 106 75 80 1102424 52 72 68 61 1102692 62 59 64 54 1102793 64 107 76 81 1103067 61 104 75 86 1103077 64 82 74 66 1103084 37 60 69 53

TABLE 31 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 49 30 90 43 1100479 57 34 71 47 1101375 59 45 74 48 1101609 86 84 104 83 1101667 84 68 100 82 1101764 85 68 93 72 1101853 65 45 78 53 1101962 79 59 92 67 1102195 111 65 98 73 1102426 76 61 79 69 1102690 53 33 80 42 1102787 78 65 106 87 1102808 65 47 88 58 1102865 92 72 101 81 1102957 75 58 81 71 1102981 76 56 94 66 1102997 85 62 97 74 1103105 68 49 85 56

TABLE 32 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 38 43 84 42 1100514 70 79 87 81 1101616 48 50 75 57 1101683 71 83 90 88 1101689 61 73 85 71 1101786 87 101 113 99 1101811 66 90 90 73 1101817 88 73 98 96 1101828 89 102 97 104 1102097 75 90 100 83 1102144 58 73 86 74 1102162 71 79 90 81 1102220 57 54 84 59 1102228 78 102 108 103 1102283 52 57 84 63 1102335 69 91 100 73 1102589 86 95 101 93 1102648 73 83 84 82 1102706 39 36 69 38 1102746 61 64 94 69 1102757 40 62 74 49 1102761 47 60 73 58 1102792 68 80 92 79 1102876 46 50 81 55 1102974 102 106 109 104

TABLE 33 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem  650528 32 42 77 39 1100475 46 51 78 37 1100508 33 28 30 29 1101718 45 40 71 49 1101808 76 87 78 78 1101821 73 75 79 68 1101912 67 74 87 53 1101927 77 80 75 75 1101958 72 66 68 44 1102073 61 68 69 63 1102074 42 47 72 42 1102110 80 88 87 78 1102385 42 58 75 40  1102555* 86 85 79 64 1102722 78 91 80 75 1102734 43 69 77 50 1102789 65 73 82 59 1102848 76 92 96 84 1102953 80 82 81 78 1103012 80 90 79 70 1103041 34 23 61 35 *Group has only 1 animal

TABLE 34 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 36 47 81 44 1101736 33 32 61 38 1102060 57 53 82  56† 1102106 50 64 78 62 1102134 94 94 98 100  1102334 77 66 85 71 1102374 61 69 104  66 1102567 68 67 81 66 1102695 52 71 88 63 1102758 59 52 78 55 1102779 39 50 86 48 1102805 70 71  84† 75 1102898 63 71  73† 70 1103000 71 82 100  77 1103006 72 63 85 72 1103072 75 73 86 66 †Average of 2 PCR points

TABLE 35 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 28 43 76 32 1101974 13 10 48 15 1102130 21 29 73 23 1102132 86 70 91 70 1102133 85 86 101 85

TABLE 36 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal Brain Number cord Cortex Cerebellum Stem 650528 40 33 78 44 1101657 28 22 66 32 1102028 33 28 63 30 1102637 40 27 69 42 1102638 39 29 95 43 1102639 34 31 121 37 1102640 56 58 75 57 1102642 67 64 87 65

TABLE 37 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal caudal Brain Number cord cortex Cerebellum Stem 650528 28 49 68 40 1100723  40† 60 62 53 1100724 45 43 69 52 1100725 28 39 60 34 1100726 57 79 67 60 1100727 58 51 80 57 1100728 38 45 67 50 1100729 37 39 63 48 1102683 31 23 55 27 †Average of 2 PCR points

TABLE 38 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal caudal Brain Number cord cortex Cerebellum Stem 650528 38 39 80 31 1102574 32 41 70 34 1102595 102 94  98† 72 1102596 103 91 97 92 1102597 89 94 96 78 1102598 39 28 62 35 1102599 40 54 78 34 1102600 37 53 75 33 1102601 50 58 80 43 1102602 70 73 95 60 1102603 94 101 97 84 1102604 108 101 108  80 1102605 102 103 106  82 †Average of 2 PCR points

TABLE 39 Reduction of human ATXN3 RNA in transgenic mice hATXN3 Expression (% control) Compound Spinal caudal Brain Number cord cortex Cerebellum Stem 650528 39 46 39  54† 1100505 46 55 41 49 1100506 57 60 37 62 1100672 37 36 46 32 1100731 35 33 32 33 1102811 19 24 29 23 1103041 36 26 37 29 †Average of 2 PCR points

Example 7: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human ATXN3 In Vitro, Multiple Doses

Modified oligonucleotides selected from the examples above were tested at various doses in A431 cells by free uptake. Also tested was comparator Compound No. 650528, a 5-8-5 MOE gapmer with mixed PO/PS internucleoside linkages complementary to human ATXN3, described hereinabove and in WO 2018/089805.

Cells were plated at a density of 10,000 cells per well, and treated with 109.4 nM, 437.5 nM, 1,750.0 nM, and 7,000.0 nM concentrations of modified oligonucleotide, as specified in the tables below. After a treatment period of approximately 48 hours, total RNA was isolated from the cells and ATXN3 RNA levels were measured by RT-qPCR.

Human ATXN3 primer probe set RTS38920 (described hereinabove in Example 1) was used to measure RNA levels. ATXN3 RNA levels were adjusted according to total RNA content, as measured by RiboGreen®. In addition, ATXN3 RNA levels were also normalized to human GAPDH levels measured by human GAPDH primer-probe set RTS104 (forward sequence GAAGGTGAAGGTCGGAGTC, designated herein as SEQ ID NO: 2804; reverse sequence GAAGATGGTGATGGGATTTC, designated herein as SEQ ID NO: 2805; probe sequence CAAGCTTCCCGTTCTCAGCC, designated herein as SEQ ID: 2806). Results are presented in the table below as percent ATXN3 RNA levels relative to untreated control cells. IC₅₀ was calculated using the “log(inhibitor) vs. normalized response—variable slope” formula using Prism7.01 software. In some cases, an IC₅₀ could not be reliably calculated and the data point is marked as “N.C.”.

TABLE 40 Dose-dependent reduction of human ATXN3 RNA by modified oligonucleotides ATXN3 level (% control) normalized to ribogreen Compound 109.4 437.5 1,750.0 7000.0 IC₅₀ Number nM nM nM nM (μM) 650528 84 67 48 38 2.03 1100673 50 21 11 9 0.10 1100914 26 12 7 5 <0.10 1101657 93 53 31 17 0.69 1102130 85 46 24 13 0.47

Example 8: Tolerability of Modified Oligonucleotides Complementary to Human ATXN3 in Rats, 3 mg Dose

Modified oligonucleotides described above were tested in rats to assess the tolerability of the oligonucleotides. Sprague Dawley rats each received a single intrathecal (IT) dose of 3 mg of oligonucleotide listed in the table below. Each treatment group consisted of 4 rats. A group of four rats received PBS as a negative control. At 3 hours post-injection, movement in 7 different parts of the body were evaluated for each rat. The 7 body parts are (1) the rat's tail; (2) the rat's posterior posture; (3) the rat's hind limbs; (4) the rat's hind paws; (5) the rat's forepaws; (6) the rat's anterior posture; (7) the rat's head. For each of the 7 different body parts, each rat was given a sub-score of 0 if the body part was moving or 1 if the body part was paralyzed. After each of the 7 body parts were evaluated, the sub-scores were summed for each rat and then averaged for each group. For example, if a rat's tail, head, and all other evaluated body parts were moving 3 hours after the 3 mg IT dose, it would get a summed score of 0. If another rat was not moving its tail 3 hours after the 3 mg IT dose but all other evaluated body parts were moving, it would receive a score of 1. Results are presented as the average score for each treatment group. A comparator compound, 650528, a 5-8-5 MOE gapmer with mixed PO/PS internucleoside linkages complementary to human ATXN3 described hereinabove and in WO 2018/089805 was also tested.

TABLE 41 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100397 1.50 1100405 1.50 1100406 1.25 1100407 2.75 1100528 1.50 1100534 2.75 1100535 3.75 1100540 3.00 1100542 1.00 1100566 3.00 1100585 0.25 1100590 2.50 1100725 3.00 1100873 1.50 1100914 3.25 1100915 5.50 1100920 2.25 1100990 4.50 1100991 3.75

TABLE 42 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1101101 4.50 1101339 5.75 1101351 2.25 1101974 2.25 1101975 1.75 1102024 2.00 1102028 0.75 1102050 5.00 1102130 2.00 1102131 2.00

TABLE 43 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1102336 2.25 1102353 1.75 1102551 3.00 1102557 2.75 1102574 3.00 1102580 1.75 1102599 0.75 1102657 1.00 1102811 2.00 1102970 3.00 1102977 0.75 1102978 1.50 1102979 1.50 1103103 3.25

TABLE 44 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100379 1.50 1100398 2.00 1100399 2.75 1100408 4.00 1100409 2.50 1100521 4.00 1100527 2.00 1100536 4.50 1100541 6.00 1100544 3.00 1100839 3.00 1101000 4.00 1101920 1.75 1102329 3.25 1102666 3.00

TABLE 45 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100571 1.50 1100572 1.25 1100667 0.00 1100730 3.25 1100732 3.25 1100809 1.25 1100864 3.25 1100865 2.75 1100907 3.25 1100911 0.50 1100980 4.00 1101054 4.00 1101065 2.75

TABLE 46 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1101121 2.25 1101122 3.25 1101350 4.00 1101352 3.25 1101411 1.00 1101657 0.25 1102084 2.50 1102090 2.50 1102128 2.75 1102198 3.00 1102562 2.00 1102563 3.50 1102612 2.25 1102667 1.75

TABLE 47 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100410 3.50 1100468 0.25 1100557 1.00 1102541 0.75 1102600 0.50 1102637 0.00 1102677 4.00 1102683 0.25 1102725 0.50 1102980 1.25 1103001 2.75 1103014 0.50 1103069 1.00

TABLE 48 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.50 1100584 0.25 1100697 0.25 1100753 0.00 1100810 1.75 1100872 1.50 1100898 2.00 1100900 1.00 1100902 0.25 1100921 0.50 1100992 0.00 1101099 3.25 1101120 2.00 1101203 1.50 1101918 1.00

TABLE 49 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100559 0.25 1101053 0.00 1101202 0.00 1101383 0.25 1101659 0.00 1101873 0.75 1102052 0.00 1102103 0.25 1102108 0.00 1102129 0.25 1102180 0.00 1102202 0.00 1102239 0.00 1102678 0.00 1102998 2.00

TABLE 50 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 650528 0.50 1100429 0.00 1100430 0.00 1100434 0.25 1100666 0.25 1100756 0.00 1100802 0.50 1100863 0.00 1100906 0.25 1102379 0.50 1102598 1.75 1102646 0.00 1102663 0.00 1102669 0.00 1102679 0.00 1102750 0.00

TABLE 51 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100369 4.00 1100479 5.00 1100505 6.00 1100508 6.00 1101375 3.00 1101721 5.75 1101853 4.00 1102690 1.25 1102706 4.50 1102808 5.00 1103041 4.75

TABLE 52 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100505 5.00 1100506 2.25 1100729 2.25

TABLE 53 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100672 0.00 1100731 3.00

TABLE 54 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.25 1100731 4.00

TABLE 55 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100723 0.50 1100724 2.25 1100728 0.75

TABLE 56 Tolerability scores in rats at 3 mg dose Compound 3 hour Number FOB PBS 0.00 1100673 0.00

Example 9: Activity of Modified Oligonucleotides Complementary to Human ATXN3 in Transgenic Mice, Multiple Dose

Modified oligonucleotides described above were tested in the ATXN3 YAC transgenic mouse model which contains the full-length human ATXN3 disease gene harboring an expanded CAG repeat (CAG84, Q84) previously described herein.

The ATXN3 transgenic mice were divided into groups of 4 mice each. Mice in each group were given a single ICV bolus of oligonucleotide at a dose of 10 μg, 30 μg, 100 μg, 300 μg, or 700 μg, and sacrificed two weeks later. A group of 3-4 mice was injected with PBS and served as the control group to which oligonucleotide-treated groups were compared. After two weeks, mice were sacrificed, and RNA was extracted from brain cortex, spinal cord, brain stem and/or cerebellum for real-time PCR analysis of measurement of RNA expression of ATXN3 using primer probe set RTS43981. Results are presented as percent change of RNA, relative to PBS control, normalized to mouse cyclophilin A measured using mouse primer probe set m_cyclo24 as previously described herein. As shown in the tables below, human ATXN3 RNA was reduced in various tissues. ED₅₀ was calculated for the compounds using the “non-linear fit of transform ED₅₀” formula in GraphPad Prism 7.01. In some cases, ED₅₀ could not be reliably calculated and is represented as “N.C.” (not calculated).

TABLE 57 Reduction of human ATXN3 RNA in transgenic mice Spinal Cord Cortex Brain Stem Cerebellum hATXN3 hATXN3 hATXN3 hATXN3 Compound Dose Expression ED₅₀ Expression ED₅₀ Expression ED₅₀ Expression ED₅₀ Number (μg) (% control) (μg) (% control) (μg) (% control) (μg) (% control) (μg) 1100673 10 72 16.3 83 62.9 88 33.6 78 N.C. 30 39 76 58 76 100 23 47 34 65 300 14 15 20 50 700 12 11 17 42 1101657 10 71 25.3 93 69.9 91 79.4 94 N.C. 30 57 76 81 77 100 36 45 51 77 300 19 23 28 49 700 19 17 25 44 1102598 10 74 28.0 91 65.0 108 113.9 98 N.C. 30 53 63 71 69 100 41 55 60 69 300 30 24 39 59 700 23 18 32 45 1102811 10 76 24.7 90 80.4 93 49.5 92 N.C. 30 47 74 67 75 100 30 51 41 66 300 17 31 25 67 700 11 16 18 62

TABLE 58 Reduction of human ATXN3 RNA in transgenic mice Spinal Cord Cortex Brain Stem hATXN3 hATXN3 hATXN3 Compound Dose Expression ED₅₀ Expression ED₅₀ Expression ED₅₀ Number (ug) (% control) (μg) (% control) (μg) (% control) (μg) 1102130 10 69 21.0 76 28.6 78 33.2 30 54 51 58 100 31 37 36 300 24 14 33 700 18 9 23

Example 10: Effect of Modified Oligonucleotides Complementary to Human ATXN3 in Cynomolgus Monkeys Following Repeat-Dose Intrathecal Injection, 13-Week Study

Cynomolgus monkeys are treated with modified oligonucleotides to determine the local and systemic tolerability and pharmacokinetics at 1 dose level, following 3 intrathecal lumbar bolus injections administered 4 weeks apart. Cynomolgus monkeys in groups of 4 are treated with either artificial CSF or modified oligonucleotide. Tissues are collected 1 week after the final injection.

Assessment of tolerability is based on clinical observations, body weights, food consumption, physical and neurological examinations including sensorimotor reflexes, cerebral reflexes and spinal reflexes, coagulation, hematology, clinical chemistry (blood and cerebral spinal fluid (CSF)), cell count, and anatomic pathology evaluations. Complete necropsies are performed with a recording of any macroscopic abnormality. Organ weights are taken and microscopic examinations are conducted. Blood was collected for complement analysis. In addition, blood, CSF, and tissues (at necropsy) are collected for toxicokinetic evaluations.

Activity of modified oligonucleotides is analyzed in brain and spinal cord tissue by measuring cynomolgus monkey ATXN3 RNA. Brain and spinal cord samples are collected and flash frozen in liquid nitrogen and stored frozen (−60° C. to −90° C.). At time of sampling, 2 mm biopsy punches are used to collect samples from frozen tissues for RNA analysis. Punches are taken from multiple brain and spinal cord regions.

Example 11. Human Clinical Trial with Modified Oligonucleotides Complementary to Human ATXN3

Ascending doses of modified oligonucleotide are evaluated in a randomized, double-blind study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics, and clinical efficacy in patients with confirmed genetic mutation in SCA3. Patient safety will be monitored closely during the study. Safety and tolerability evaluations include: physical examination and standard neurological assessment, vital signs, ECG, AEs and concomitant medications, Columbia Suicide Severity Rating Scale (C-SSRS), CSF safety labs, plasma laboratory tests, urinalysis, and neuroimaging studies. 

1-77. (canceled)
 78. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.
 79. The modified oligonucleotide of claim 78, which is the sodium salt or the potassium salt.
 80. A modified oligonucleotide according to the following chemical structure:


81. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: Ges ^(m)Teo Teo ^(m)Teo Aes Tds Tds Tds Ads Tds Tds ^(m)Cds Tds ^(m)Cds Ads Aeo Geo Tes Aes ^(m)Ce (SEQ ID NO: 423); wherein, A=an adenine nucleobase, ^(m)C=a 5-methyl cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE modified sugar, d=a 2′-deoxyribose sugar, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 82. A population of modified oligonucleotides of claim 78, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
 83. A pharmaceutical composition comprising a modified oligonucleotide of claim 78 and a pharmaceutically acceptable diluent.
 84. The pharmaceutical composition of claim 83, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 85. The pharmaceutical composition of claim 84, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
 86. The pharmaceutical composition of claim 84, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
 87. A population of modified oligonucleotides of claim 80, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
 88. A pharmaceutical composition comprising a modified oligonucleotide of claim 80 and a pharmaceutically acceptable diluent.
 89. The pharmaceutical composition of claim 88, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 90. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
 91. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
 92. A population of oligomeric compounds of claim 81, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
 93. A pharmaceutical composition comprising the oligomeric compound of claim 81 and a pharmaceutically acceptable diluent.
 94. The pharmaceutical composition of claim 93, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 95. The pharmaceutical composition of claim 94, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
 96. The pharmaceutical composition of claim 94, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
 97. A method comprising administering to a subject a pharmaceutical composition of claim
 83. 98. A method of treating a disease associated with ATXN3, comprising administering to a subject having or at risk for developing a disease associated with ATXN3 a therapeutically effective amount of a pharmaceutical composition according to claim 83 and thereby treating the disease associated with ATXN3.
 99. The method of claim 98, wherein the disease associated with ATXN3 is a neurodegenerative disease.
 100. The method of claim 99, wherein the neurodegenerative disease is SCA3.
 101. The method of claim 99, wherein at least one symptom or hallmark of the neurodegenerative disease is ameliorated.
 102. The method of claim 101, wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.
 103. The method of claim 98, wherein the subject is human.
 104. A method of reducing expression of ATXN3 in a cell comprising contacting the cell with a modified oligonucleotide of claim
 78. 105. The method of claim 104, wherein the cell is a human cell. 